FUNCTIONAL ATLAS OF ORPHAN NUCLEAR RECEPTORS Release Date: June 7, 2001 RFA: RFA-DK-01-026 (Reissued as RFA-DK-06-503) National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Aging Letter of intent: October 17, 2001 Application Receipt Date: November 19, 2001 PURPOSE The purpose of this initiative is to develop a Functional Atlas of Orphan Nuclear Receptors emphasizing understanding and cataloging of structure, tissue distribution, specificity, and function. Nuclear hormone receptors, their ligands, and relevant accessory proteins play important roles in development and aging, metabolism, and disease, and comprise a large superfamily of receptors for a multitude of hormones, xenobiotics, lipids, and other known and unknown ligands. Knowledge of the function, structure, and specificities of these receptors can serve as the basis for the development of therapeutics to treat diseases, including diabetes, obesity, osteoporosis, heart disease, and prostate and breast cancer. While a great amount of information has already been uncovered, recent advances continue to provide a wealth of new data that must be collated and analyzed. Thus, further understanding of receptor specificity, ligand selectivity, interaction with cytoplasmic and/or nuclear accessory proteins, chromatin, and the transcriptional machinery, will require development of a unique database to collect and integrate this information. It is anticipated that this initiative will enhance coordination with emerging genetic information from the human (and other) genome effort(s). This initiative will focus specifically on one sub-group of the superfamily, the orphan nuclear receptors (ONR). HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA, (Functional Atlas of Orphan Nuclear Receptors), is related to the priority area of: Chronic Diseases. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. In addition, collaborators from foreign institutions are permitted. MECHANISM OF SUPPORT The funding instrument to be used for this program will be a Research Program-Cooperative Agreement (U19), an assistance mechanism (rather than an acquisition mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. The U19 allows for support of a series of components designed to explore a cohesive theme. Under the cooperative agreement approach, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the sections "TERMS AND CONDITIONS OF AWARD", OBJECTIVES AND SCOPE", and "SPECIAL REQUIREMENTS." Except as otherwise stated in this announcement, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps/). Funding is anticipated before the end of FY 2002. The total project period for applications submitted in response to the present RFA may not exceed 5 years. The anticipated award date is September 30, 2002. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. FUNDS AVAILABLE For Fiscal year 2002 $2.5 Million (Total Costs = Direct + Facilities and Administrative Costs) will be committed by NIDDK to fund one application in response to this RFA. In addition, the National Institute on Aging has committed $0.5 Million (Total Costs) in support of this initiative, for a total of $3.0 Million (Total Costs). Although this program is provided for in the financial plans of the NIDDK and NIA, the awards pursuant to this RFA are contingent upon the availability of funds and receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Nuclear receptors comprise a large family of hormone-dependent and - independent transcription factors responsible for reproduction, growth, differentiation, and homeostasis. The nuclear receptors are part of a large superfamily consisting of receptors for steroid hormones (estrogen, androgen, adrenal glucocorticoid, aldosterone, and progesterone; ER, AR, GR, MR, and PR, respectively), nuclear hormones (vitamin D, retinoids, thyroid hormone; VDR, RAR/RXR, TR, respectively), and orphan nuclear receptors (peroxisome proliferator activated receptor or PPAR, lipid receptors, COUP-TFI/II, SF-1, etc.). The latter have functions in cells, during development and in the adult, but with no, or only poorly, defined ligand(s). While some orphan receptors have recently been classified as responding to defined ligands (e.g. PPAR?), the identity of true natural ligands in most instances remains to be elucidated. Studies in model organisms have suggested that members of this superfamily have a long evolutionary history, are well conserved in lower organisms, and constitute a significant portion of known genomes (Tsai and O'Malley, Ann. Rev. Biochem. 63:451-486, 1994; McKenna et al. J. Steroid Biochem Mol Biol 69:3-12, 1999). With the rapid onset of knowledge of the human genome, it is clear that nuclear receptors are present in abundance in humans, as well (Lander et al., Nature 409:860, 2001), with both known and unknown functions. Moreover, it is anticipated that with further annotation of the human genome other orphan nuclear receptors will be discovered. While some of these receptors will prove to have redundancies (e.g. Brown, et al. JCI 106:73-79, 2000), many will be found to be unique with specific localizations and/or functional implications as well as implications for disease (Lazar, J. Investig. Med. 47:364-368, 1999). Others may have temporal specificities associated with developmental roles (Zhou et al., Neuron 24:847-859, 1999). As additional genomic information emerges, expression studies utilizing proteomics tools become an important component of discovery. Although primarily functioning as transcription factors, it has become clear that the biology of these receptors is complex: they are often bound to chaperone proteins in the cytoplasm, and/or to DNA in the nucleus; they may bind to DNA as monomers, dimers, or heterodimers--- with or without ligand; they may interact with any of a number of different classes of nuclear accessory and/or chromatin remodeling proteins; the presence or absence of ligand can define interactions with other proteins which foster the ability of the receptor to activate or repress gene expression; and alterations in the receptor, the ligand, or various of the accessory proteins, such as co-activators and co-repressors, can have profound effects on development, and protein/lipid/carbohydrate metabolism, and in diseases such as prostate and breast cancer, and diabetes, obesity, heart disease, and osteoporosis, as well as processes associated with aging. The receptor, the ligand, and relevant accessory proteins can also serve as the basis for the development of therapeutics to treat disease. To do so, further research is required to fully understand the molecular mechanism of action of these receptors, the underlying basis for tissue specificity of action, the nature of cellular co-activator or co- repressor usage, and the role(s) these may play in the development, progression, and treatment of disease. With this in mind, it has become clear that the vast amount of information already available, coupled with the new information emerging from model organisms and from the human genome project, calls for a large-scale, collaborative effort designed to develop, categorize and integrate knowledge of orphan nuclear receptors. To this end, the U19 encompasses research projects and shared resources designed as part of a collaborative effort to address the objectives of the program. Objectives and Scope Two overriding objectives govern this initiative: 1) collation and characterization of information already in hand, and 2) new research to more fully understand the role(s) of orphan nuclear receptors in health, disease, and aging. In developing a Functional Atlas of Orphan Nuclear Receptors, the long-term goal is to focus on orphan receptors (e.g. PPAR, FXR, LXR, SXR, SF-1, CAR, COUP TFI/II, etc.), as well as the cofactors and the ligands with which many interact to complete a functional loop. Among these cofactors are those present in the nuclear compartment (coactivators, corepressors, chromatin modifying proteins and RNA transcripts, linkers, methylases, histone modifying enzymes, etc.), as well as those in the cytoplasmic compartment (chaperones, binding proteins, kinases/phosphatases). Beyond the scope of this present initiative, but certainly relevant in functional contexts, is consideration of the nuclear (VDR, RAR, RXR, TR), and steroid (ER, AR, GR, MR, PR) receptors, as they intersect with ONRs. Insights into the structures of several receptors both bound and unbound to ligand and/or cofactor(s) have been revealed by x-ray crystallographic and NMR studies. Discovery of natural and artificial ligands has added much to our understanding of function. For some Orphan Nuclear Receptors, role(s) in disease has preceded knowledge of putative ligand(s), as for PPAR? and its role in adipogenesis and insulin resistance in Type 2 diabetes mellitus. Indeed, based on less than complete knowledge, several ligands directed at PPAR? have already been developed for use as insulin sensitizing agents in the treatment of Type 2 diabetes (e.g. thiazoladinediones;TZDs). The general concept of Selective Receptor Modulators (SRMs) has evolved rapidly to include clinical use of drugs with selective actions on nuclear receptor function, such as TZDs for Type 2 diabetes and tamoxifen for estrogen- dependent breast cancer. With greater knowledge of nuclear receptor structure, tissue specificity, and function, in general, it will be possible to develop more powerful and effective SRMs, many of which will be relevant to ONRs. Finally, while much is known about the expression and function of many of the members of this family, studies exploiting gene knock-outs in mouse transgenic models have revealed redundancies and levels of compensation that confound our full understanding of the physiology of many of the integral components of the hormone action loop. Although it is desirable to create a unified Functional Atlas for the entire Nuclear Receptor Superfamily, limited resources initially available for this initiative do not at this time allow for development of such a comprehensive program. While considerable information exists regarding the structure and function of the steroid receptors and the nuclear receptors, less information is currently available for the orphan nuclear receptors (ONR). The ONRs have developed a central importance as a consequence of their role(s) in development (organogenesis) and metabolism (e.g. lipid and carbohydrate; see Chawla et al., Cell 103:1-4, 2000), as well as aging. With this in mind, the immediate focus of this initiative will be with development of a Functional Atlas of Orphan Nuclear Receptors. To do so it is envisioned that the final program will include research and development in the following areas: o Determination of tissue specificity: understanding and cataloging levels and extent of expression in different cells/tissues. o Preference in cofactor usage: tissue specificity and context of coactivator and/or corepressor usage; role of putative ligand(s) in cofactor recruitment (binding/dissociation) and function. o Receptor domain structure and function: DNA and/or ligand binding, transactivation, cofactor association. o Receptor/DNA interaction: roles in and effects of chromatin remodeling cofactors on regulation of transcription; roles of receptor dimerization and (homo-, hetero-) dimer partner usage (e.g. with nuclear receptors such as RXR). o Regulation of expression: role(s) in development and aging; signaling cross-talk; ligand feedback; receptor subtype expression. o Physiology/pathophysiology: issues of redundancy and/or compensation; mutations and polymorphisms which affect metabolic function and/or disease. o Target for therapeutics: putative ligands, partial agonists, antagonists, subtype specific factors (e.g. Selective Receptor Modulators or SRMs). o Orphan receptors in lower and model organisms: functional correlations with mouse and/or human. o New gene discovery based on data mining through genome databases. o Use of appropriate proteomics tools to determine the function of orphan nuclear receptors, associated cofactors, or gene targets. While some of these objectives represent efforts to collect and catalog what is already known, others require research efforts that may involve novel and innovative approaches to develop needed information. In order to maximize the resources available in a rich and diverse research community, it is anticipated that a defined structure must be developed, which will allow for development of a series of components, defined as research projects and shared resources. The latter will include Administrative, Bioinformatics (required elements), and other shared resources as proposed by the applicant. The former (collectively called Research Components) include bridging and pilot projects (at the host institution or through appropriate subcontracts to other sites) directed at delineation of specific components of the overall program (see SPECIAL REQUIREMENTS). Since the primary objective of this large- scale collaborative effort will be data integration, each contributing project will include a plan that addresses data integration and an interface with the Bioinformatics Resource. Full integration of data with the Bioinformatics Resource will facilitate rapid dissemination of new information, development of new hypotheses, and allow for data mining via a web-based interface. Given the breadth of the task, a large-scale collaborative effort (i.e., the U19 mechanism) is best suited for development of a Functional Atlas of Orphan Nuclear Receptors. The objectives listed above suggest a scope for this initiative, and they do not preclude additional objectives proposed in applications responsive to this RFA. To develop a Bioinformatics Resource for the Functional Atlas of Orphan Nuclear Receptors it will also be necessary to include research and development of the following objectives: o Development of a functioning relational database as the basis of a Bioinformatics Resource for the Functional Atlas of Orphan Nuclear Receptors. o Development of (and/or use of existing) software to enable collection and analysis of data from many different sources and formats, including cDNA and protein sequences, microarrays, histopathological analysis, structural biological analyses (e.g. NMR, X-ray crystallography), and other databases and analytical tools. o Regular curation of existing and emerging information, including evaluation and annotation of data and incorporation into appropriate databases; integration of information from many different sources; database and interface design and implementation. o Development of appropriate algorithms to allow for rapid data mining and in silico analyses of structural and functional relatedness and/or gene discovery. o Development of algorithms to facilitate interactive and integrated analyses of function (e.g. metabolic flow charts). o Providing for the maximal interoperability to facilitate the ability to rapidly search other databases for related information relevant to nuclear receptors, including functional databases, lower (model) organisms databases (e.g. Flybase (http://www.fruitfly.org/), and the human genome project (e.g. National Center for Biotechnology Information). o Development and maintenance of web tools and a web site for the Functional Atlas which facilitates use on any platform. o Provision of capability, by investigators of the Functional Atlas program, to readily enter and access data. Since the mechanism for this program is a cooperative agreement in the form of a Research Program (U19), an overall collaborative protocol will be developed at the time of initiation of funding by a Steering Committee (see TERMS AND CONDITIONS OF AWARD), composed of the awardee(s), individual project principal investigators, and the NIDDK Program Scientist. It is anticipated that intense and meaningful interactions between and among the collaborating investigators involved in the U19 will result in achievement of progress at a rate and in a fashion not possible for the individual. While some of the information to be developed is anticipated to be of a descriptive, but necessary, nature, other work will involve new approaches and conceptual leaps that will be driven by the collaborative nature of the interactions. In the application a detailed explanation of the rationale should be provided, along with definitive and progressive landmarks, with a timeline for the achievement of the goals (see below and APPLICATION PROCEDURES). Research Components, together with Shared Resources, should be integrated to produce a collaborative effort that maximizes the individual efforts and facilitates fulfillment of the overall objectives of the Functional Atlas. The expertise appropriate for this research program includes knowledge of the molecular endocrinology, pharmacology, histology, and pathophysiology of Orphan Nuclear Receptors. In addition, expertise in development and use of transgenic models and of mouse genetics is essential. Expertise in computational biology, bioinformatics, genomics, proteomics, and phenotypic analysis is also highly recommended. SPECIAL REQUIREMENTS GENERAL ORGANIZATION OF THE FUNCTIONAL ATLAS OF ORPHAN NUCLEAR RECEPTORS RESEARCH PROGRAM (U19) Development of a Functional Atlas of Orphan Nuclear Receptors requires considerable effort to organize. A U19 application should be headed by a Principal Investigator (PI), who is an expert in the field. As a cooperative agreement, the primary governing body for the program will be a Steering Committee, which will have responsibility for overall study design and policy decisions (described in more detail under TERMS AND CONDITIONS OF AWARD ). Members of the Steering Committee will include the PIs of research components and shared resources, and key independently supported collaborators, as well as representative(s) of the NIH. Since the overall purpose of this initiative is to develop a Functional Atlas of Orphan Nuclear Receptors, a Bioinformatics Resource will serve as the focal point for the collaborative efforts, and will be a required Shared Resource. This Bioinformatics Resource will be the focal point for data collection and analysis, and serve as the primary interface with the general research communit(ies)y. Research in the form of individual projects (bridging and pilot) will be used to acquire new information and fill in gaps, where needed. In order to give structure to the collaborative arrangements inherent in a U19, it is anticipated that at least two meetings/year of the Steering Committee (study investigators and the NIDDK) will take place. These meetings will commence once the Steering Committee has had an initial organizational meeting at or near the time funding is initiated. Applicants should formally state their willingness to participate in such activities and plans for these meetings should be included in the budget requests of the individual applications (see below in TERMS AND CONDITIONS). The purpose of these meetings will be to provide periodic updates on progress, resolve issues related to sharing of resources and data, and modification (if necessary) of study design and/or timetable, develop needs for additional expertise and coverage through subcontracts, as well as development and entry of data with the Bioinformatics Resource. To promote the development of a collaborative program among the award recipients, a number of issues need to be addressed in the application, as discussed below. Applicants should discuss the rationale for their individual and collaborative approaches, how they will interact effectively with the Steering Committee and the Bioinformatics Resource, and state their willingness to follow the common protocol that will be agreed upon by the Steering Committee and that would apply to all participants in the U19. The U19 application should include elements of the following categories: RESEARCH COMPONENTS: 1. Bridging projects (e.g. Gene Expression, Tissue Specificity, Physiology, Structure/Function) may be requested for collaborative activities that would function as supplements to the ongoing, funded, independent work in the laboratories of participating investigators. These bridging projects to the laboratories of participating investigators are to add to or bridge the intellectual and technological approaches of the collaborative program. They are not meant to be stand-alone research efforts but are to be subprojects that tie (or enhance the contribution of) the independent work of the participating investigator to the large-scale collaborative program. These bridging projects may be from 2-5 years in duration, as needed. 2. Pilot projects (e.g. Imaging, Ligand Discovery, Data Mining) may be requested for investigators in an area deemed important to the collaborative project, to add elements where gaps exist, or to add investigators with critical knowledge or expertise. These need not be from individuals having a research background in the area of the collaborative program. These projects may not exceed $75,000 in annual direct costs and must be limited to no more than three such projects. Each project should be of sufficient scope to qualify as an independent research effort. It is primarily intended to allow the collaborative program to address gaps in the overall scope, or to add investigators outside the scientific mainstream of the project area in a mode that will allow them to develop independent research in the area of the collaborative program. While funding for an individual pilot may run for three (3) years, at the discretion of the steering committee, it is expected that the principal investigator of a project will seek R01 funding during the period of the collaborative project, based on the results obtained from the project. Such R01 funding should include plans for further interaction with other components of the Functional Atlas. SHARED RESOURCES: The organizational structure of the collaborative project may assume a variety of different forms, all focused on addressing the scope described above. In addition to required Bioinformatics and Administrative Resources, other Shared Resources may be included, as needed (e.g., Transgenic Animals, Microarray, Proteomics) to speed progress on the scientific goals of the project, add additional capability to the collaborative project by bringing in new or improved technology and/or by standardizing data among different research teams among the collaborating or participating laboratories. This might include such technologies as high-throughput gene chip microarrays, imaging or transgenic methodologies. Other types of resources might be for instrumentation, genomics, proteomics, high- throughput assays, or computational/bioinformatics/modeling capabilities not already provided by a Bioinformatics Resource. Any such requests should be strongly justified in terms of contributions to achieving the long-term goals of the Functional Atlas of Orphan Nuclear Receptors, to increasing the synergy of the collaborative project, or to enhancing overall cost effectiveness. The major focal point for shared resources should be a Bioinformatics Resource, which will be devoted to data collection, coordination, analysis, and to dissemination of information developed by the various components of the collaborative program. Each of the sub- and/or participating projects should have plans for interfacing with this Bioinformatics Resource. TERMS AND CONDITIONS OF AWARD These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. 1. Collaborative Responsibilities The administrative and funding instrument used for this program is a cooperative agreement (U19-Research Project), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIDDK purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partnership role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Program Scientist. 2. Participating investigator: A research project (U19) application will include a team of investigators who will contribute to and benefit from participation (collaboration) in the program. The members of the collaborative project will be referred to collectively as participating investigators, although one will be the Principal Investigator. It is expected that each of the participating investigators will hold an externally peer reviewed and funded research grant in the area of the project, with the majority funded through regular research grants supported by NIDDK, other NIH institutes and centers, and other governmental and private agencies. Exceptions to the rule of external funding may include participating investigators from industry, foreign institutions or allied fields not traditionally supported by the NIH (e.g., physics, computational biology, mathematics). Each participating investigator must provide evidence of their commitment to the project and a listing of organizational resources that will be committed to the project. Participating investigators will work together via the Steering Committee to develop workable guidelines for achieving the objectives of the collaborative program. Participating investigators must agree to abide by the policies and rules set up for the collaborative program and to the terms and conditions described in this document to be eligible to participate. During the period of the award, a participating investigator whose independent research support terminates may continue as a participating investigator at the discretion of the Steering Committee and with the approval of the NIDDK Program Scientist. Funds from this award are not to be used to support the independent project of such an investigator. It is expected that new participating investigators will be added to the collaborative project over the period of the award as deemed appropriate by the principal investigator and steering committee and with the approval of the NIDDK Program Scientist; these additions will be reported in the annual progress report. 3. Awardee Rights and Responsibilities: The PI, and participating investigators, will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award. The PI will assume responsibility and accountability to the applicant organization officials and to the NIDDK for the performance and proper conduct of the research supported by the project in accordance with the terms and conditions of the award. The PI and one participating investigator from each participating project of the program will participate as permanent, voting members of the Steering Committee (see below), will attend the initial Planning Meeting and any subsequent Steering Committee meetings in the first and subsequent years, as needed. The PI will be responsible for contributing to and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee, and will be responsible for close coordination and cooperation with other of the Functional Atlas of Orphan Nuclear Receptors program and NIDDK staff. Awardees will retain custody of, and have primary rights to, the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Investigators conducting biomedical research frequently develop unique research resources. The policy of the PHS is to make available to the public the results and accomplishments of the activities that it funds. Principles and guidelines for recipients of NIH research grants on obtaining and disseminating biomedical research resources can be found at: http://www.nih.gov/od/ott/RTguide. The NIDDK reserves the right to require the transfer of animals, reagents, and pertinent data that are generated as the result of participation in research supported under these awards to an eligible third party, in order to preserve the continuity of the research project. Third parties supported under these awards must be informed of this right. The Functional Atlas group will be expected to provide the NIDDK and the NIA with data in a uniform, usable platform throughout the course of the studies and after the termination of the studies supported by this RFA. Effective conduct of Functional Atlas goals, as defined in this RFA and following Steering Committee action, will require considerable electronic communication of data and other information among the Functional Atlas and between the various constituent components and the NIDDK. The Functional Atlas members will be required to demonstrate that they have the ability to transfer data accurately and effectively. 4. NIDDK Staff Responsibilities The NIDDK Program Scientist will have substantial scientific- programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. The dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Program Scientist. The NIDDK Program Scientist will have voting membership on the Steering Committee and, as determined by that committee, its subcommittees; will coordinate and facilitate the Functional Atlas programs, attend and participate as a voting member in all meetings of the Functional Atlas Steering Committee, and provide liaison between the Steering Committee, the Functional Atlas investigators, and the NIDDK. The NIDDK Program Scientist and the NIDDK will ensure that there is an effective, Internet-based mechanism to enable electronic communication among the Functional Atlas, and with the NIH. The NIDDK Program Scientist will assist the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require coordinated action. Since the NIDDK Program Scientist will be a participating member of the Steering Committee, to avoid any conflicts of interest, a separate NIDDK Project Officer will have responsibility for the analysis, review, and approval of all budgetary actions. This Project Officer will be separate and distinct from the NIDDK Program Scientist, and will not be a member of the steering committee. NIDDK and NIH extramural staff with relevant scientific expertise, or who manage research grant programs that relate scientifically to the goals of the Functional Atlas program, will form a separate NIDDK Functional Atlas Working Group. The Group will meet regularly to review the progress of the Functional Atlas, and to advise the NIDDK Program Scientist of scientific developments and opportunities that may enhance the achievement of the goals. The NIDDK Functional Atlas Working Group will collaborate with the NIDDK Program Scientist to organize and implement the workshops and symposia recommended by the Functional Atlas Steering Committee, and to provide a liaison between the appropriate research communit(ies)y and the members of the Functional Atlas, as well as the External Scientific Working Group. The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of a major breach in the protocol or substantial changes in the agreed-upon protocol with which the Institute does not agree. 5. Governance A Steering Committee, composed of the Project PI, the participating project principal investigator(s), and the NIDDK Program Scientist will be the main governing board of the study and will have primary responsibility for developing common research designs, protocols and manuals, facilitating the conduct and monitoring of studies, reporting study results, and resolving issues that may arise. The principal investigators from the participating projects, any relevant subcontract projects, and the Bioinformatics Resource, and the NIDDK Program Scientist will each have one vote. The chairperson, who will be someone other than an NIDDK staff member, will be selected by the Steering Committee. Subcommittees will be established by the Steering Committee, as appropriate; the Program Scientist will serve on subcommittees, as he/she deems appropriate. The collaborative protocols will be developed by the Steering Committee. Data will be reviewed and submitted centrally to the Bioinformatics Resource. Protocols will define rules regarding access to data and publications, as well as ensuring rapid dissemination of data to the general research community. It is anticipated that awardees will have lead responsibilities in all joint tasks and activities, as assisted by the NIDDK Program Scientist, where appropriate. Awardees will be required to accept and implement the common protocol and procedures approved by the Steering Committee. 6. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the Institute may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with the NIDDK member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDDK, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html. A completed copy of the updated Guidelines is available at: http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups, if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants an Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. GUIDELINES FOR RESEARCH USING HUMAN PLURIPOTENT STEM CELLS At the present time, the NIH cannot fund research involving the use of stem cells derived from human embryos.. This restriction does not apply to: human adult stem cell research; derivation or use of pluripotent stem cells from human fetal tissue; or animal stem cell research. For the most current information on policies related to research using human pluripotent stem cells, investigators should access the National Institutes of Health Stem Cell Information site at: http://stemcells.nih.gov/index.asp Details on the approval process and the procedures for submitting the required documentation of compliance are at the following URL address: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by October 17, 2001 a letter of intent that includes a descriptive title of the proposed research; name, address, and telephone number of the Principal Investigator; identities of other key personnel and participating institutions; and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows NIDDK staff to estimate the potential review workload and to plan the review. The Letter of Intent is to be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd Room 752, MSC 5452 Bethesda, MD 20892 (For Fed Ex and UPS use 20817) 301-594-8897 301-480-3505 fax FC15Y@NIH.GOV APPLICATION PROCEDURES U19 application should demonstrate essential elements of unity and interdependence that, through the collaborative effort, result in a greater contribution to program goals, as defined in the objectives for the Functional Atlas, than would occur if each project were pursued individually. Specifically, the relationship and contributions of each Research Component and Shared Resource to the goals of the Functional Atlas of Orphan Nuclear Receptors should be discussed. These programs provide support for research projects as well as shared resources and facilities, which are available to individual projects comprising the program. Shared Resources must provide essential functions, services, techniques, determinations or instrumentation that will enhance at least 2 individual research projects. A Bioinformatics Resource is required. In this component, details as to how data that are generated from individual projects will be stored, organized, analyzed, or visualized should be described. An Administrative Resource is required to assist in allocation of resources, coordination of projects, provide logistical support for meetings and workshops, and coordination with subcontracts. Subcontract budgets should be listed on a separate page, and the subcontract Facilities and Administrative (F&A) costs should be calculated and listed in the usual place as part of the direct costs of the budget (see TABLE OF CONTENTS ). Preparation of Application Applications are to be submitted on the standard research grant application form PHS 398 (rev. 4/98). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: grantinfo@nih.gov and on the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html. A response to this RFA should consist of an application that, in addition to or in lieu of part of the items requested in the PHS 398 (http://grants.nih.gov/grants/funding/phs398/phs398.html), includes: Description, Performance Site(s), and Key Personnel: On page 2, describe briefly the proposed large scale-collaborative research project (Abstract). List all key personnel involved in the collaborative project; use a continuation page if needed. Table of Contents. Prepare a Table of Contents for the overall project that includes the items listed below. Page limitations are given in the specific descriptions for each section. SAMPLE TABLE OF CONTENTS SECTION I Face Page Table of Contents (Overall program) Detailed Budget for First 12-Month Period Budget Estimate for Each Year of Project Summary of All Other Sources of Support Biographical Sketches (PI and all participating investigators, key personnel and collaborators) SECTION II Overall Program Goals Research Plan Program Summary Administrative Management Plan Project Management Plan Preliminary Studies Plan for Data Sharing and Intellectual Property Institutional Environment and Resources Organization and Administrative Structure SECTION III Shared Resources Shared Resource A Title Page (Title, Resource Director) Description of Resource Budget for the First 12-Month Period Budget Estimate for Each Year of Requested Support Role and Justification for the Shared Resource Plan of operation Integration with the program Gender and Minority Inclusion Children Inclusion Human Subjects Vertebrate Animals Consortium/Contractual Arrangements Consultants/Collaborators Shared Resource B, etc Title Page (Title, Resource Director) Description of Resource Etc. SECTION IV. Research Components Bridging Project 1 Title Page (Title, Project Leader) Description of Research Plan/List of Key Personnel Detailed Budget for First 12-Month Period Budget Estimate for Each Year of Requested Support Resources and Environment Research Plan Plan for integration with overall program Gender and Minority Inclusion Children Inclusion Human Subjects Vertebrate Animals Consortium/Contractual Arrangements Consultants/Collaborators Bridging Project 2, etc. Title Page (Title, Project Leader) Etc. Pilot Projects (up to 3) Title Page (Project 1, 2, etc) Detailed Budget for First 12-Month Period Budget Estimate for Each Year of Requested Support Resources and Environment Research Plan Plan for integration with overall program Gender and Minority Inclusion Children Inclusion Human Subjects Vertebrate Animals Consortium/Contractual Arrangements Consultants/Collaborators Literature Cited with complete titles and authors for the entire program. Checklist The major areas to be listed in the Table of Contents above, appear below in capital letters. BUDGET ESTIMATES: Specific examples of allowable costs that may be requested include: In addition to the overall budget for the entire Functional Atlas program, include a separate budget for each bridging project, the (up to 3) pilot projects and the Shared Resources. Applications for U19- Research Project awards may not request more than $3.0 million in annual total costs (exclusive of subcontract F&A costs requested as a direct cost by the applicant organization) for any year of the award. Salaries for support personnel required for coordination and maintenance of the program, such as secretaries or administrative assistants, may also be included, as necessary, in the Administrative Resource. Specific Items that may be included: 1. Salaries for the principal investigator, members of the steering committee, participating investigators, technical, and support personnel commensurate with their level of effort in the large-scale collaborative program. 2. Pilot projects to investigators relevant to the Functional Atlas can be without current independent research support in the area. Pilots must not exceed $75,000 in annual direct costs and must be limited to no more than three such projects per application. They may include travel of personnel (e.g. predoctoral students, postdoctoral trainees, and investigators) to different laboratories to gain specialized expertise. These grants may be for no more than 3 years each, and may be replaced by such new projects as the Steering Committee deems appropriate to achieve the goals of the overall program (see Project Management Plan). The Pilot and Feasibility projects should be listed with a common budget, each project not to exceed the individual cap of $75,000. 3. Travel to and conduct of regular meetings of the steering committee and regular meetings of the participating investigators. 4. Shared Resource facilities (examples: instrumentation, genomics, proteomics, model organism, high-throughput assay, or computational/bioinformatics). 5. Electronic media resources to allow participation of off-site laboratories and/or the means necessary to establish collaboratory capabilities and for information dissemination. Travel to and conduct of regular meetings of an external advisory working group. Composite budget. Use Form Page 4, "DETAILED BUDGET FOR INITIAL BUDGET PERIOD," of Form PHS-398 to present the total budget for all requested support for the first year. For each category such as "Personnel," Equipment," etc., give the amount requested for each Resource unit and each component project, with subtotals. For consortium arrangements involving other institutions or organizations, include total (direct and facilities and administration) costs associated with such third-party participation in the "Consortium/Contractual Costs" category. Note that consortium costs will count against the $3.0 Million Total Costs cap. Costs for purchased services should be itemized under "Other Expenses." Use Form Page 5, "BUDGET FOR ENTIRE PROPOSED PROJECT PERIOD," of Form PHS-398 to prepare a budget, by category, that provides totals for each year of requested support. The costs for the Pilot and Feasibility studies should be reported as one total figure for the (up to) three such projects. Requests for any increases in succeeding years must be justified in the individual component subprojects (bridging projects and pilot projects) and Resource budgets. Individual budgets for shared resource and research components: For the first year budgets of each of the shared resource and research projects, use Form Page 4 of the PHS-398. Use Form Page 5 of the PHS- 398 to report the budgets of each of the projects and shared resources for total project period (years 02-05). Budget justifications and explanations: Describe the specific functions of all key personnel, including consultants, collaborators, and technical staff. Provide justifications for requested equipment. For years 02-05 of the application, justify any significant increases or decreases in any category over the first year budget. Applicants must budget for travel and per diem that will allow the Principal Investigator, and designated participating or senior investigator to participate in at least two steering committee meetings each year. Applicants should plan to attend a workshop or symposium every year in years 2-5. BIOGRAPHICAL SKETCHES AND LETTERS OF COMMITMENT: Biographical sketches and letters of commitment must be included from all participating investigators indicating their willingness to follow guidelines and procedures established for the large-scale collaborative project. The format described in the PHS398 application for modular applications should be followed for this information. RESOURCES AND ENVIRONMENT: Complete the "Resources" page of PHS-398 for the overall large-scale collaborative project, including both the host institution and any participating institutions. Briefly describe the features of the institutional environment(s) that are relevant to the effective implementation of the proposed program. As appropriate, describe available resources, such as clinical and laboratory facilities, participating and affiliated units, patient populations, geographical distribution of space and personnel, and consultative resources. RESEARCH PLAN In the PHS398 application kit a 25 page limit for the Research Plan is described. In lieu of that limitation, for the Functional Atlas, a forty (40) page limit is in effect for the following four sections (PROGRAM SUMMARY, ADMINISTRATIVE MANAGEMENT PLAN, PROJECT MANAGEMENT PLAN, and PRELIMINARY STUDIES). Investigators should endeavor to be concise. For other sections please follow the instructions for each individual part of the application, as below. PROGRAM SUMMARY: A summary describing the goals and operation of the program. Explain how the scope of this initiative will be addressed and how the approach of using a large-scale collaborative agreement is critical to its solution. Discuss the range of scientific expertise to be brought to bear on the research problem. Explain the interactions that will occur between investigators at the host site and at the participating sites. Explain how each element of the large-scale collaborative project will contribute to successful attainment of its goals. Explain the programmatic value of the Shared Resources, and the Research Components (bridging and pilot projects). Explain how the information resulting from the collaborative efforts of the entire program, to include the laboratories of the participating investigators, will be integrated into the Bioinformatics Resource and with comprehensive program, as a whole. Discuss how information generated by the collaborative program will be disseminated to the scientific community, in general. ADMINISTRATIVE MANAGEMENT PLAN: Describe the structure, organization, and operation of the program. Describe the organizational framework and provide an organizational chart detailing the flow of information within the collaborative program. Discuss arrangements between the collaborating institutions that are important to effective operation of the U19. Detail the usage of the Shared Resources by the participating investigators. Include any outreach efforts to provide access to the Shared Resource to investigators outside the collaborative program. Discuss how the views of the scientific community impacted by the collaborative program will be considered. PROJECT MANAGEMENT PLAN: Provide a timeline for the program, as a whole, and for each component, defining yearly landmarks to be used to assess progress. Explain how progress in the bridging and pilot projects and efficiency of the Shared Resources will be tracked. Include an evaluation plan to determine how the collaborative program is progressing. Discuss the plan for evolving landmarks. Explain how the External Scientific Working Group will be used in updating the project management plan. Explain how decisions will be made to add/delete participating investigators and to respond to changes in short term goals that research findings will make necessary. Provide a plan for assessment of the bridging and pilot studies with emphasis on how it will be decided what duration they should have and whether and how they should be replaced. PRELIMINARY STUDIES: Provide any preliminary studies/data that may be relevant to the overall program. Data should be in a readily interpretable form, with legends and appropriate identification of figures/tables in the text. Specific page limitations have been established for the following sections: PLAN FOR DATA SHARING AND INTELLECTUAL PROPERTY (two page limit): The principal investigator and steering committee should (1) propose a plan for providing access to the data and information generated by the large-scale collaborative project to the members of the project and the scientific public; (2) address if or how intellectual property rights will be exercised; (3) discuss guidelines for licensing of joint inventions; (4) discuss procedures for settling of intellectual property disputes; (5) discuss the existence of any pre-existing intellectual property rights, including options to for-profit research sponsors; and (6) propose a plan for disseminating the technologies, assays, and associated reagents developed under this RFA INSTITUTIONAL ENVIRONMENT AND RESOURCES (two page limit): The environment and resources at the host institution that will be available to this program should be described. The environment and resources available at collaborating institutions should be provided in the descriptions of those specific projects. SHARED RESOURCES SHARED RESOURCE A. BIOINFORMATICS RESOURCE (required; ten page limit): This Resource will be required for data accumulation, analysis, coordination and dissemination. Dissemination of information on techniques, scientific findings, and methodologies is a vital component of the large-scale collaborative program. Effective use of computer technology, print media, and telecommunications are relevant. Describe the staffing (including a Resource Director, as well as any professional or technical personnel and their duties), facilities, and resources that will be devoted to this goal. Indicate plans to make results of research or other unique features of the collaborative project available for as wide an audience as possible. Describe how data generated by the Shared Resource and Research Components will be processed into the information to be disseminated. Discuss how data will be reviewed prior to inclusion in the bioinformatics database. Discuss plans for dissemination of published and unpublished data. SHARED RESOURCE B. ADMINISTRATIVE RESOURCE (required; five page limit): This Resource must be directed by the principal investigator. Include the objectives of the Resource, a description of its staffing and services to be provided to other resources and to the participating investigators. Communicating the objectives of the collaborative program and fostering opportunities for collaboration are encouraged. Expenses associated with the operation of the steering committee, meetings of all or subgroups of the participating investigators, and meetings and operation of the External Scientific Working Group would fall under the Administrative Resource. SHARED RESOURCE C (and others): There is a 10 page limit per Resource. Provide specific titles for any proposed scientific Shared Resources (e.g., instrumentation; genomics; proteomics; model organism; high- throughput assay; or computational, modeling, or bioinformatics), along with a designated Resource Director who possesses expertise in the area of each Resource. Describe the professional and technical staff to be involved in the Resource(s), and their duties. Include plans to utilize the Resource(s), including services that will be provided, and to whom, and their bearing on productivity and quality of the collaborative research effort. RESEARCH COMPONENTS BRIDGING PROJECTS (ten page limit for each bridging project): A bridging project should be designed to support work in the laboratory of a participating investigator relevant to the objectives of the overall program. For all proposed projects, the underlying rationale and potential impact of the studies should be specifically addressed. The need for the bridging project to tie (or enhance) the independent work of the participating investigator to the goals of the collaborative program must be described. Essential information for the research plan should include specific aims, background and significance, preliminary studies, and research design and methods, and may be presented as a combined summary of these sections emphasizing the following: Describe the new research proposed in the bridging project and explain how this work more fully integrates the participating investigator’s independently supported work into the overall theme and objectives of this collaborative Research Program. A bridging project should extend the participating investigator’s independent work in a direction(s) relevant to goals of the Functional Atlas program. A bridging project to do more of what the investigator is already doing should be considered only if there are extraordinary circumstances that make it essential for the effective functioning of the large-scale project. If the participating investigator’s work is already closely tied to the large-scale project, a bridging project should not be needed. Substantial new research projects should not be submitted for bridging projects; these should be submitted as regular R01 applications, even if they add value to the large-scale project. Projects must be described in sufficient detail to permit evaluation through the competitive peer-review process. For each bridging project undertaken as part of the collaborative program, also to be included are sections (where appropriate) that address: Gender and Minority Inclusion for Research Involving Human Subjects, Inclusion of Children as Participants in Research Involving Human Subjects, Human Subjects, Vertebrate Animals, Consortium/Contractual Arrangements, Consultants. Literature Cited should be included in the citations for the entire program, at the end of the application. PILOT PROJECTS (five page limit for each pilot project for the research plan: specific aims, background and significance, preliminary studies, and research design and methods; maximum of three pilot projects per large scale collaborative program): Pilot projects may support the work of investigators not already supported in the area of the collaborative program but who have unique skills or expertise that add to the collaborative effort. For all proposed projects, the underlying rationale and potential impact of the studies should be specifically addressed. How the pilot project will add new elements essential to achieving the goals of the collaborative program must be described. Projects must be described in sufficient detail to permit evaluation through the competitive peer-review process. For each pilot project undertaken as part of the collaborative project, include the following sections: Abstract (one paragraph), Specific Aims, Background and Significance, Preliminary Studies, Research Design and Methods, as well as Gender and Minority Inclusion for Research Involving Human Subjects, Inclusion of Children as Participants in Research Involving Human Subjects, Human Subjects, Vertebrate Animals, Consortium/Contractual Arrangements, Consultants. Literature Cited should be included in the citations for the entire program, at the end of the application. INSTITUTIONAL COMMITMENTS: Letters signed by authorized business officials of each of the participating investigators' institutions committing support to the large-scale collaborative project must be included. Applicants for proposals that include consortium arrangements should refer to the NIH Grants Policy Statement appendix on consortium arrangements at: http://grants.nih.gov/grants/policy/nihgps/part_iii_5.htm#Consortium. OTHER SUPPORT OF PARTICIPATING INVESTIGATORS: For the principal investigator, steering committee members, participating investigators, and heads of Resource resources, provide a listing of all other support for each participant in the usual NIH format for non-modular applications (see http://grants.nih.gov/grants/funding/phs398/phs398.html); support for other investigators such as postdoctoral students should not be listed. For the relevant grant support that allows participating investigators to be part of the large-scale collaborative project, provide the specific aims of the project and describe in sufficient detail for evaluation the relationship of the funded grant to the goals of the proposed collaborative Research Program (U19). METHOD OF APPLYING The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of applications. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. Enter the RFA number on the label. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive Room 1040 - MSC 7710 Bethesda, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all five sets of any appendix material must be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 752 Bethesda, MD 20892-5452 Applications must be received by November 19, 2001. If an application is received after the due date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. NIH Review Criteria for Investigator-initiated projects: The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewer will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. In addition to the criteria below, in accordance with NIH policy, all applications will also be reviewed with respect to the following (where relevant): o Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. o For applications with foreign components: Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. REVIEW CRITERIA FOR THE RESEARCH PROJECT-COOPERATIVE AGREEMENT (U19) Overall Project 1. Significance. Does this collaborative Research Program adequately address the central question of this initiative, i.e. development of a Functional Atlas of Orphan Nuclear Receptors, in a way that would be difficult to address by separate grants? Do the arrangements for data sharing maximize the impact of the collaborative program? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the scientific aims of the collaborative program? Is the project management plan adequate and comprehensive? Is the administrative framework appropriate and designed to integrate the various components? Do landmarks articulate key indicators set for appropriate times that will demonstrate significant forward progress for the collaborative program? Are the plans to monitor and evaluate progress of the collaborative program adequate? Will the Bioinformatics Resource support the objectives of the Functional Atlas? Are the plans to share the data and findings with the larger community adequate? How will the group take the views of the scientific community impacted by the large- scale collaborative program into consideration? 3. Innovation. Will the collaborative program challenge existing paradigms or develop new methodologies or technologies? Will the collaborative program attack the problem in a significantly new way? What will be the value added over individual grants? 4. Investigators. Is the principal investigator's major research activity within the research area of the collaborative program? Is the principal investigator well suited to the scientific and administrative leadership required to carry out this work? Is the level of effort proposed for the principal investigator and the members of the steering committee appropriate? Is the work proposed appropriate to the experience level of the collaborative program's research and technical staff? Are the research grants of the participating investigators within the area of the collaborative program? Are the participating investigators well chosen for their roles in the collaborative program? Is the plan to add and delete participating investigators to and from the collaborative program satisfactory? 5. Environment. Will the proposed collaborative program take advantage of unique features of the scientific environments of the component projects? Is the level of institutional support adequate? Are the requested Shared Resource facilities critical to achieving the scientific goals of the collaborative program; are they cost effective? Is access to the Shared Resource facilities appropriate? In addition, the following criteria will be considered for merit review: The commitment to the program by the principal investigator and the members of the steering committee will be a consideration. For applications that are multi-institutional or that involve industry, the adequacy of plans to resolve intellectual property issues will be a consideration. The commitment of the host and participating universities to supporting the large scale collaborative program will also be considered: this would be reflected in efforts to work out ahead of time potential intellectual property issues and to remove any institutional barriers to the establishment and healthy maintenance of the collaborative program. Review Criteria for Research Components (Bridging and Pilot Projects) 1. Significance. Does this project address an important problem relevant to the overall scope of the Functional Atlas? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the achieving the goals of the collaborative program? Will the bridging project tie or enhance the independent work of the participating investigator to the collaborative program, or will the pilot project add an essential missing aspect to the collaborative program? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the program? 3. Innovation. Does the collaborative nature of the project enhance potential innovation? 4. Investigator. Is the participating investigator appropriately trained and well suited to carry out a collaborative project? Is the work proposed appropriate to the experience level of the participating investigator and other researchers (if any)? 5.Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Review Criteria for Shared Resources. 1. Facilities within the Shared Resource compared to the state of the art; the contributions of the Shared Resources to fulfilling the goals of collaborative program. 2. The extent to which Shared Resource units promote greater collaboration and cohesiveness among the participating investigators. Does this resource promote an economy of scale? Are there unique aspects of the resource that contribute to achieving the overall goals of the program? 3. Qualifications, experience, and commitment to the large-scale collaborative program mission of the investigators responsible for the Shared Resources and their abilities to devote the required time and effort to the program. 4. Appropriateness of the budgetary requests. AWARD CRITERIA Award criteria that will be used to make funding decisions include: o scientific merit (as determined by peer review) o program priorities o program balance o availability of funds SCHEDULE Application Receipt Date: November 19, 2001 Peer Review Date: Feb.-March 2002 Advisory Council Date: May 2002 Earliest Anticipated Award Date: September 30, 2002 INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues relevant to NIDDK to: Ronald Margolis, Ph.D. Senior Advisor, Molecular Endocrinology Division of Diabetes, Endocrinology, and Metabolism National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 6107 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8819 FAX: 301-435-6047 E-mail: rm76f@nih.gov Direct inquiries regarding fiscal matters to: Cheryl Chick Division of Extramural Activities NIDDK 6707 Democracy Boulevard, Rm. 714 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8825 FAX: 301-480-3504 E-mail: cc149o@nih.gov Direct inquiries regarding programmatic issues relevant to NIA to: Frank Bellino, Ph.D. Biology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 2C231 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: FB12A@nih.gov Direct inquiries regarding fiscal matters to: Linda Whipp Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: lw17m@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 for DEM (NIDDK), and No. 93.866 (NIA). Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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