COMPREHENSIVE PROGRAMS IN BETA CELL BIOLOGY Release Date: August 14, 2001 RFA: RFA-DK-02-014 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov/) Letter of Intent Receipt Date: February 13, 2002 Application Receipt Date: March 13, 2002 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is seeking to intensify investigator-initiated collaborative research aimed at understanding the signaling pathways in the adult pancreatic beta cell, and how these signaling networks are integrated by the different cell types of the pancreatic islet. This initiative is intended to support large multi- component projects of outstanding investigators with innovative, high impact studies focused on the beta cell and the adult pancreatic islet; to attract established investigators who can bring novel or advanced techniques, tools and concepts from other areas of research to the study of beta cell biology; and to foster interdisciplinary approaches to the study of beta cell biology. Use of emerging genomic and proteomic methods to elucidate beta cell specific trafficking events, signaling pathways, and novel components of the islet microenvironment required for proper beta cell function is strongly encouraged. The ultimate goal is to use this increased understanding of the biology of the pancreatic islet to develop novel approaches to the treatment of diabetes. In further support of this initiative, the NIDDK will hold a workshop, Beta Cell Biology in the 21st Century: Engineering a Pathway to Greater Understanding , on November 26-28. An important goal of this workshop is to identify areas of research opportunity in the adult pancreatic beta cell. Prospective applicants to this RFA are encouraged to attend this important workshop http://www.betacellbiology.niddk.nih.gov. 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 Request for Applications (RFA), COMPREHENSIVE PROGRAMS IN BETA CELL BIOLOGY, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, 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 (PI). MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) R01 award mechanism to support a full range of applications as outlined below. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA is a one- time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2002. The R01 mechanism is highly flexible and can be used to accommodate a range of project sizes and organizational structures. In this initiative, the NIDDK is encouraging the formation of collaborations among scientists with a variety of different expertise and ideas, so that multifaceted approaches, diverse skills, unique tools, and special resources can be used to investigate the biology of the adult beta cell. Numerous organizational structures are possible. For example, the R01 can be used for large projects in which all the work is coordinated by a single PI, and collaborating projects are located at a single institution. When collaborating investigators are at different institutions, but the project is to be conducted under the auspices of a single PI, a large R01 with several subcontracts may be requested. This allows for integration of multi-disciplinary approaches and a variety of resources under the direction of one PI. With this scenario, the PI is responsible for ensuring that the scientific goals are met, and for resource allocation. Furthermore, short- term high-risk potentially high pay off studies, as well as studies aimed at the development of novel technologies or reagents can be submitted as part of a larger project. When a project is better served by an organizational structure where several senior investigators are located at different institutions, and/or desire to have the same administrative status as principal investigator, the interactive research project grant (IRPG) may be used. IRPGs are groups of individual R01s that share a common theme AND demonstrate a high level of interaction. The IRPG program is designed to foster interdisciplinary collaborative research activities where the exchange of data, materials, and ideas is more important than extensive, shared resources and central oversight. The IRPG is described at http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html can be used for this RFA, except that the R29 mechanism will not be allowed, and only new projects (no competing continuation applications) may be included. The NIDDK can choose to fund individual R01 applications outside the collaborative arrangement owing to their special scientific merit and programmatic needs and balance. IRPGs that are not successful in the RFA can be revised and resubmitted at the normal R01 deadlines for revised applications. The revised applications will be reviewed by standing NIH study sections, rather than by an NIDDK convened special study section. In addition, it is not guaranteed that individual RO1 projects of a revised IRPG will be reviewed by the same study section. Applicants are encouraged to develop the organizational structure that works best to promote the overall research goals of the project. The organizational structure and a plan for oversight of the entire project should be detailed in the application. FUNDS AVAILABLE The NIDDK intends to commit approximately $6 million (total costs) in FY 2002 to fund 2 to 8 new awards in response to this RFA. An applicant may request a project period of up to 5 years. It is anticipated that the size of the awards will vary because the nature and scope of research programs proposed will vary. The requested budget for a large R01 grant with or without multiple subcontracts or the combined budgets for an IRPG may be up to $2 million direct costs per year (excluding F&A costs for subcontracts). Successful applicants will have the opportunity to request additional funds for the development of infrastructure and bioinformatics resources, and for the purchase of large equipment. Well justified requests designed to accelerate the progress/productivity of the project will be considered on a case-by-case basis, contingent on the availability of funds. Principal Investigators anticipating the submission of applications with direct cost budgets of $500,000 or more per year MUST consult with the program official listed under INQUIRIES prior to extensive preparation of the application, in order to obtain prior approval to submit such an application. Although the financial plans of the NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds, and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Beta cells of the adult pancreas are found in the islets of Langerhans in close contact with other endocrine cells, specifically, the alpha and delta cells that secrete the counter-regulatory hormones, glucagon and somatostatin, and a small population of poorly understood endocrine cells that secrete pancreatic polypeptide. Inter- and intracellular signaling by the cells of the pancreatic islet in response to glucose and other metabolites and hormones, as well as the interaction of these cells with their microenvironment, are all thought to be critical to the proper functioning of the beta cell. The beta cell plays a central role in the regulation of energy metabolism. The controlled release of insulin in response to a meal or to other cellular signals is essential for the uptake of glucose from the blood, storage of glycogen and lipid, and regulation of DNA and protein synthesis. Failure of the beta cell to properly synthesize and secrete insulin in response to changes in nutrient status results in diabetes mellitus. Since ideal glucose homeostasis is rarely attained by insulin therapy, patients with diabetes remain at risk for the development of serious long-term complications, such as kidney failure, loss of limbs, blindness, and heart disease. This RFA is a direct response to recommendations of the Congressionally- established Diabetes Research Working Group detailed in its report Conquering Diabetes, A Strategic Plan for the 21st Century , http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm. One of the extraordinary research opportunities recommended by the plan was to better define signaling in the beta cell. Subsequently, the NIDDK initiated the Comprehensive Beta Cell Project to develop a greater knowledge of beta cell development, structure, and function with the goal of developing new approaches to the treatment of diabetes. This current initiative is one of several ongoing initiatives. The Functional Genomics of the Developing Endocrine Pancreas project http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-99-007.html is using genomics approaches to enumerate all the unique protein coding regions in the developing and adult, human and mouse beta cells, and to clone the associated mRNAs. The ongoing results of this effort can be found in the Endocrine Pancreas Consortium Database , http://www.cbil.upenn.edu/EPConDB. Information in this database may help to identify new areas of research opportunity and promote additional studies in the beta cell and pancreatic islet. Another component of the Comprehensive Beta Cell Project, the Beta Cell Consortium, is designed to bring together multidisciplinary teams of researchers to gain a better understanding of beta cell development and differentiation in hopes of obtaining an unlimited supply of new beta cells or islets for use in long-term treatment of type 1 diabetes mellitus (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-01-014.html). Studies directed at improving methods for islet cell transplantation (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-99-006.html), at developing gene transfer approaches to enhance islet transplantation (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-01-006.html), and for developing new technologies for beta cell imaging (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-02-002.html) have been issued. Much of the beta cell research reported to date has been carried out in cell lines derived from insulin-producing tumors (e.g., mouse and rat insulinomas), and in modified neuroendocrine cells (e.g., mouse AtT20 cells). These cell lines have proven very useful for in vitro studies of insulin secretion. However, these culture systems do not accurately recapitulate all of the normal physiology of the beta cell in the pancreas. Interaction of the various endocrine cell types of the islet with each other, and with their microenvironment, is critical to the proper functioning of the adult beta cell. The challenge that is upon us now is to understand more fully the complete signaling environment of the pancreatic beta cell. To achieve this formidable goal it will be necessary to determine which proteins are expressed specifically in the beta cell, as well as in the other endocrine cells of the adult pancreatic islet. It is also essential to understand the intra- and intercellular signaling pathways that lead to responses such as insulin secretion and amino acid transport; To elucidate the many signaling pathways initiated at the plasma membrane, and to determine the molecules (proteins, lipids, small metabolites and ions) important for integration of these signals in the cytoplasm, and in the nucleus where complex cellular machinery regulates the transcription and translation of beta cell specific genes; To understand the interactions between the different cell-types of the pancreatic islet and the extracellular matrix, both in time and space, and to elucidate how these signaling pathways may be different in healthy islets and in the dysfunctional islets resulting from the development of diabetes mellitus. The use of gene inactivation and protein knock-in and knock-out experiments to study the role of newly identified beta cell proteins in whole animal physiology will be important. Further more, although it remains instructive to use immortalized beta cell lines to characterize potential ligands and intracellular binding partners for newly discovered beta cell receptors, to identify potential substrates for beta cell specific enzymes, as well as to try to understand the complex signaling networks functioning in the beta cell, all findings will ultimately need to be confirmed in a physiologically relevant milieu such as freshly isolated islets, islets produced via differentiation of progenitor cells or in improved beta cell models, as they become available. Scope of Research The NIDDK intends to support multidisciplinary investigator-initiated projects that explore fundamental aspects of beta cell biology. Investigators applying to this RFA are encouraged to use genome-wide studies (genomics and proteomics), advanced imaging techniques, analytic methods, and state-of-the art cell biological approaches to investigate broad areas of research opportunity in the beta cell biology in order to: o Obtain a comprehensive knowledge of the many cell-specific surface molecules involved in the response of beta cells to extracellular signals, determine their interaction partners, and investigate how these interactions are impacted by nutrients and hormones, as well as by regulatory signals from other endocrine cells of the islet. o Delineate the signaling networks in the cytoplasm and the nucleus of the beta cell responsible for amplification and integration of signals initiated at the plasma membrane both in time and space, and elucidate how these signaling pathways differ in healthy beta cells/islets, and in the altered or dysfunctional beta cells/islets resulting from or contributing to the development of diabetes mellitus. o Understand the roles played by cell-cell contact and extracellular matrix components in the islet, in signaling to and from the beta cell. o Understand the metabolic networks and the control of flux of substrates, intermediates, and products in the beta cell and the pancreatic islet in response to nutrients, hormones, growth factors, cytokines, and neurotransmitters. Topics of research that may be part of these comprehensive projects may include, but are not limited to the following: o Explore the function of newly identified proteins specific for the beta cell. For example, determine their subcellular localization, their interaction partners, and role in beta cell function. o Determine the hormone, growth factor, and/or cytokine receptors and/or channels that are important for beta cell integrity and function. o Elucidate the role of cytoskeletal elements and motor assemblies in the normal functioning of the beta cell. o Develop and use transgenic and knockout animal models to investigate the function of various beta cell proteins in their physiological context(s). o Explore which co-activators and co-repressors are responsible for regulating the transcription of beta cell specific genes. o Develop and use model cell systems to study how different extracellular matrix components or synthetic substrata impact beta cell survival and function. An example might be to develop a successful, functioning co- culture of two or more pancreatic islet cell types. o Investigate the extent to which the different cell populations in the pancreatic islet function as a synchronous and integrated unit coordinating their responses to nutrients through changes in electrical activity, and the synthesis and release of insulin and other hormones. o Investigate the normal physiology of the individual cell populations that constitute the pancreatic islet, study the impact of the development of diabetes on gene and protein expression levels, and predict how normal and diseased beta cells respond to various metabolic challenges, nutritional states, and drug interventions. o Study proteins specific to the beta cell that are involved in glucose sensing, transcription of insulin responsive genes, or maintenance of the beta cell phenotype. SPECIAL REQUIREMENTS Recipients of this award, as well as designated key personnel or senior investigators, are expected to attend annual Comprehensive Studies in Beta Cell Biology meetings to be held in Bethesda, Maryland, along with institute staff and other NIDDK supported investigators. The goal of these meetings will be to facilitate progress by providing a forum for sharing ideas, technology, skills, tools, data, and biological reagents among investigators focused on various aspects of Beta Cell Biology. Therefore, applicants must budget for travel funds that will allow the principal investigator, and other key research scientists, to participate in these meetings. 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 are 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 complete copy of the updated Guidelines are 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. 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. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. PRE-APPLICATION WORKSHOP A workshop will be held prior to the submission deadline for grants responding to this RFA. The workshop, Beta Cell Biology in the 21st Century: Engineering a Pathway to Greater Understanding, will be held on November 26- 28, 2001 on the NIH campus in Bethesda, Maryland at the Natcher Conference Center. The purpose of the workshop is to highlight current state-of-the-art research relevant to inter- and intracellular signaling networks in the adult pancreatic beta cell and other related cellular systems. The workshop will bring together investigators from multiple disciplines with interests in numerous aspects of cell biology such as vesicle trafficking and secretion, nutrient regulation of gene transcription, whole cell genomics and proteomics, animal models of disease, and signaling networks within cells, between cells, and in relation to the extracellular environment. Through this workshop, the NIDDK hopes to establish a research agenda for the pancreatic beta cell, and to help foster interdisciplinary activities to further these objectives. Additional information about the workshop can be found at http://www.betacellbiology.niddk.nih.gov. The workshop will conclude with a public briefing for those interested in responding to this RFA. While attendance is encouraged, it is not required that prospective applicants attend the workshop. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator(s); the 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 a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/01) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants with the modifications listed below if preparing an IRPG or large R01 with subcontracts. Potential applicants are strongly encouraged to contact program staff for pre-application guidelines to help ensure that applications will be responsive to the NIDDK mission and intent for this program. Applications requesting $500,000 or more in direct costs for any year MUST contact the NIDDK program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the staff that the NIDDK will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and who agreed to accept assignment of the application. Special Instructions to Applicants Applicants should state their willingness to share data with the community at large by timely submission of data to public databases or by making the information available to the scientific community in another way. Applicants should also state their willingness to share freely reagents such as knock-in and knock-out mice, expression vectors, and antibodies. INSTRUCTIONS FOR PREPARING LARGE R01S WITH SEVERAL SUBCONTRACTS The following instructions address ONLY the parts of the PHS 398 research grant application form for which information about the proposed interactive research is requested. All other parts of the grant application should be prepared according to the instructions in the PHS 398 booklet (rev. 5/01). The application should specify the administrative and organizational structure that will be used to support the research, and the synergies enabled by the structure. It is anticipated that these projects will be multi-disciplinary and will draw on a variety of resources. Thus, a well thought-out and carefully described organization will be required. The PI is responsible for ensuring that scientific goals are met, and for developing and managing a decision-making structure and process that will allow resources to be allocated (and reallocated, if necessary) to meet those goals. The application should explain how different components of the organization, including key personnel, will interact, why they are essential to accomplishing the research, and how the combined resources create capabilities that are more than the sum of the parts. If any of the components is physically separated from the others (i.e., different departments or institutions), the application should address how that separation will be managed. The NIDDK does not specify a specific organizational structure, preferring that applicants develop the structure they feel will best promote the research. However, applicants should note that the effectiveness of the proposed structure will be a criterion of the evaluation prior to an award and will be monitored after an award is made. A timeline for the project should be presented. This timeline should indicate how the project's goals can be met within the time frame of the grant. The timeline will also assist the investigators, NIDDK, and its advisors in evaluating progress toward the project's goals. In many cases applicants may choose to present explicit, quantitative milestones that can be evaluated. If the application is to be a multi-component RO1 or an RO1 with two or more large subcontracts, the narrative detailing the integrated activities of all projects (a-d) can be up to 40 pages. Please note that there is no requirement to submit this maximum number of pages. Concise, articulate applications are desired. INSTRUCTIONS FOR INTERACTIVE RESEARCH GRANT PROJECTS (IRPG) An IRPG should consist of at least two investigator-initiated applications for independent research on related topics, with a formalized agreement to collaborate in specific ways to enhance the achievement of the goals of all of the projects. The collaboration may involve limited shared resources. The IRPG, therefore, offers a means of promoting collaborative efforts between or among projects that are scientifically related, while providing a record of independently obtained awards and retaining the research autonomy of each principal investigator. Each principal investigator may apply for competing supplements to support promising new research directions as they evolve. Other benefits of the IRPG program include the establishment of collaborations on an equal footing at separate sites (including foreign locations) and the possibility of transferring an award with the principal investigator to another institution without disrupting the IRPG group. Furthermore, each participating investigator may benefit because the IRPG establishes a larger framework of reference for the proposed work and fosters formal collaborations tailored to achieving investigator-initiated research objectives. Instructions for preparing an IRPG application are described in http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html and can be used for this RFA except that the R29 mechanism will not be allowed, only new projects (no competing continuation applications) may be included in the IRPG. For components requesting greater than $250,000 direct costs in any year must follow the detailed budget directions found in the traditional PHS 398 application instructions. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. 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 RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed, 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 must be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. 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 the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of this RFA. All applications will be judged on the basis of the scientific merit of the proposed project and the documented ability of the investigators to meet the RESEARCH OBJECTIVES. Although the technical merit of the proposed protocol is important, it will not be the sole criterion for evaluation of a study. Other factors considered to be important for review include demonstrated expertise in signaling, endocrinology, cell biology, physiology, transgenic methodologies, mouse genetics, functional imaging, or beta cell biology; a multi-disciplinary team of collaborators; substantial interactions among collaborating researchers; and demonstration of appropriate facilities and resources. For IRPG applications and applications with distinct subprojects/subcontracts, the initial review group will evaluate the scientific merit of each individual effort. Additionally, the initial review group will consider the overall strength and likelihood of effective collaboration and the potential importance/contribution of the individual projects to the success of the overall effort. Any core facilities or shared resources will be assessed for their quality, cost-effectiveness and utility to the overall effort. As part of the initial merit review, all applications will 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 NIDDK Advisory Council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. To ensure that applications from this Comprehensive Beta Cell Biology program are evaluated appropriately, the standard NIH review criteria will be considered as adapted below. This RFA strongly encourages collaborative studies and thus the organizational structure and plans for collaboration as a means of meeting the program goals will also be evaluated. In the written comments reviewers 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. (1) Significance: Does this study address an important problem in beta cell biology? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? What is the scientific gain from combining multiple components (i.e., the degree of interrelatedness and synergy among the components and the appropriateness of the organizational design)? Is the management plan appropriate and of high quality for the type of project proposed? Where appropriate, are adequate bioinformatics plans to store, organize, analyze, or visualize data that is generated from the projects presented? (3) Innovation: Does the project employ novel concepts, approaches or methods in signaling and cell biology? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies that will advance the field toward a cellular replacement for diabetes? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Have collaborations been established or consultants identified to provide appropriate depth and breadth of scientific expertise required for the project? Where appropriate, is the PI appropriately qualified to lead and coordinate the activities, and develop and implement the management plan, as required for the project’s success? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Are there adequate resources available, including space, equipment, services, infrastructure, and facilities? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? (6) Collaboration: What is the likelihood of effective collaboration among the investigators? Is there evidence of active collaboration? What is the likelihood that the collaborative effort will achieve the goals of the research project? (7) Data Sharing: Do investigators state their willingness to submit data to a public database in a timely fashion or make the information available to the community at large in another way? Do the investigators agree to share reagents such as knock-out mice, plasmids and antibodies? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The 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 in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o The adequacy of the proposed plan to share data, if appropriate. SCHEDULE Letter of Intent Receipt Date: February 13, 2002 Application Receipt Date: March 13, 2002 Peer Review Date: July, 2002 Council Review: September, 2002 Earliest Anticipated Start Date: September 30, 2002 AWARD CRITERIA The intent of this RFA is to enable the NIDDK to assemble research projects composed of highly qualified individuals or teams of investigators whose complementary scientific skills and expertise will enable them to gain a comprehensive understanding of the molecular basis of pancreatic beta cell biology, and to generate new reagents and research tools that could result in the prevention and treatment of diabetes. Applications recommended by the NIDDK Advisory Council will be considered for award based upon (a) scientific and technical merit; (b) the importance of the proposed research in beta cell biology; (c) the degree of originality and innovation in project design; (d) the creativity of the approaches and technologies for the development of reagent, assays, and animal models; (e) the likelihood for substantial contribution by the applicants to a successful Comprehensive Studies in Beta Cell Biology Program; (f) the evidence for willingness to work cooperatively; (g) the quality and availability of research infrastructure and resources;(h) the availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Carol Renfrew Haft Program Director Division of Diabetes, Endocrinology and Metabolic Diseases National Institutes of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Room 605 6707 Democracy Blvd. MSC-5460 Bethesda, MD 20892-5460 Telephone: (301) 594-7689 FAX: (301) 480-3503 E-mail: cr84g@nih.gov Direct inquiries regarding review issues to: Dr. Francisco O. Calvo Chief, Review Branch Division of Extramural Activities National Institutes of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 E-mail: fc15y@nih.gov Direct inquiries regarding fiscal matters to: Mr. Ephraim Johnson Grants Management Specialist Division of Extramural Activities National Institutes of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Room 726 MSC-5460 6707 Democracy Boulevard Bethesda, MD 20892-5460 Telephone: (301) 594-8868 E-mail: ej47e@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 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 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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