CELL-SPECIFIC DELINEATION OF PROSTATE AND GENITOURINARY DEVELOPMENT Release Date: January 5, 2000 RFA: DK-00-015 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Environmental Health Sciences Letter of Intent Receipt Date: March 21, 2000 Application Receipt Date: April 21, 2000 THIS RFA USES THE MODULAR GRANT CONCEPT AND INCLUDES DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The prostate and other organs of the genitourinary tract are highly heterogeneous tissues, consisting of many cell types. Better understanding of the properties of the individual cell types and their interaction, particularly during development, is likely to lead to new approaches to prevent and treat diseases of these organs. This RFA is to encourage the development of new research tools and methods to study development and biology of the prostate and genitourinary tract. Strategies to be supported include systematic assessment of gene expression in specific cell types in the developing prostate and genitourinary tract; methods to tag individual cell types for purification, analysis, and characterization; tools to manipulate gene expression in vivo in individual cell types; and development of clinically relevant cell lines. HEALTHY PEOPLE 2000 The NIH is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a national activity for setting priority areas. This RFA, CELL-SPECIFIC DELINEATION OF PROSTATE AND GENITOURINARY DEVELOPMENT is related to the priority areas of "Chronic Debilitating Illnesses" and "Cancer." Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit 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. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and exploratory research grant (R21) mechanisms. Except as otherwise noted in this announcement, awards will be administered under policies as stated in the NIH Grants Policy Statement. R01 applications submitted in response to this RFA may not request a total project period of more than 3 years. In general, the maximum budget request for R01 applications should be limited to $350,000 in direct costs, excluding indirect costs on consortium arrangements, for each budget year. Exploratory research grant (R21) applications may not exceed 2 years for the total project period. The maximum budget request for R21 applications may not exceed $100,000 in direct costs for each budget year. The R21 grant mechanism may be used by new investigators or experienced investigators to develop pilot and feasibility studies for new and innovative approaches to prostate and genitourinary development. R21 applications generally are expected to have little preliminary data and are reviewed based on the development of hypotheses and supporting literature. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH's National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC Program Director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The anticipated award date is September 29, 2000. FUNDS AVAILABLE The NIDDK and NIEHS intend to commit approximately $4 million in FY 2000 to fund 3-4 new research project grants (R01) and 8-10 new exploratory research grants (R21) in response to this RFA. Although the financial plans of the NIDDK and NIEHS 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. RESEARCH OBJECTIVES A. Background Although our understanding of the molecular mechanisms that underlie early development of the vertebrate embryo has advanced dramatically, there has been much less progress in clarifying the processes that orchestrate the formation of the elaborate structures that make up many of the body's organ systems, including the genitourinary system. The prostate, kidney, bladder, and other organs of the genitourinary tract share common embryological origins, developing from the metanephric blastema, Wolfian and Mullerian ducts. A number of genes critical for the early differentiation of cells in the genitourinary tract have been identified, but the molecular processes and cell interactions that allow for the development of the full cellular complexity of the mature organs are poorly understood. The major goal of this initiative is to ensure that research tools are available so that a broad range of innovative methods can be applied to studying prostate development. Elucidating early steps in genitourinary tract development and subsequent steps in determining and differentiating prostate cell lineages is expected to identify genes important in prostate diseases, particularly those associated with abnormal growth, such as benign prostatic hyperplasia, prostate cancer, and other malignancies of the genitourinary tract. The cellular heterogeneity of the prostate and other organs of the genitourinary system creates special challenges for studying disease and normal physiology. The development of methods that account for the spatial and cellular complexity of these tissues is critical if new techniques for systematic study of gene expression are to be effectively applied to studying developmental events. Many interesting genes are likely to be expressed at very low levels, either at key stages of development or in highly restricted cellular locations. Therefore, strategies are needed to deal with both anatomical complexity, such as laser capture microdissection, and cellular heterogeneity, such as use of cell-specific promoters for cell tagging and isolation methods. Goals of these approaches would be in part to isolate homogeneous cell populations for library construction, EST sequencing, and assaying gene expression. There is also a need to develop techniques to visualize RNA distribution within these tissues, bioinformatic methods to visualize topologic results, and new methods to acquire material from archival samples. The major focus of this initiative is to develop tools for research in the mouse, since a wide variety of genetic and genomic approaches are possible in this species. Particularly relevant for this initiative are methods to manipulate the mouse genome. However, in view of the importance of studying gene expression in human disease, this initiative will also consider R21 pilot and feasibility studies of human material. Other species may offer unique advantages for developing methods to study cellular heterogeneity of the prostate. Studies using other species will be considered responsive to this RFA provided that a rationale is given for using the alternative species. B. Objectives and Scope This RFA encourages the development of new research tools and methods to study the early stages of development of the genitourinary tract and subsequent development and differentiation of prostate cell lineages. Strategies to be supported include methods to systematically assess gene expression in specific cell types in the developing prostate and genitourinary tract; methods to tag individual cell types for purification, analysis and characterization; tools to manipulate gene expression in vivo in individual cell types; and development of clinically relevant cell lines. Specific goals of this initiative are to develop the following research resources for the mouse: 1. Methods to tag and isolate specific cell types in the developing genitourinary tract and prostate; 2. Methods to systematically assess gene expression for the major cell types of the developing genitourinary tract and prostate; 3. A systematic catalog of cell-specific patterns of gene expression in the early stages of genitourinary tract development and in each cell type of the developing and adult prostate. These efforts are expected to include cDNA library construction and EST sequencing as appropriate; 4. Bioinformatic capacity to ensure that the research community has access to gene expression information; and Sharing strategies to ensure that other research tools are available. Research project grants (R01) will support the major objectives of this RFA. Funded investigators will be expected to participate in a cooperative initiative to achieve these goals. The final program, developed by the group of grantees, will utilize the strengths of individual investigative teams, for example in cell isolation, library construction, EST sequencing, in vivo manipulation of gene expression, and bioinformatics. Grantees are expected to develop strategies to determine the extent to which existing EST and cDNA resources adequately represent genes expressed in specific cell types. It is anticipated that the group of grantees will collectively develop a plan to focus additional EST sequencing efforts for maximum yield. Smaller, pilot exploratory research grants (R21) will support development of new strategies and innovative approaches to meet additional goals of the RFA, and to provide special expertise to help direct the larger centers in early prostate or genitourinary biology. Such pilot projects might include, for example: 1. Generation of cell-specific antibodies by phage display, and purification of cells by flow cytometry; 2. Development of validated, cultured cell lines with patterns of gene expression similar to in vivo cells; 3. Identification of cell-specific promoters, tagging of specific cells in vivo by GFP fusion proteins, and development of methods for inducible modification of gene expression in vivo; 4. Development of reagents to trace cell lineage during development, purify stem cells, and develop lineage-specific cell culture models; 5. Development of methods to retrieve information from archived biopsies; 6. Development of methods to visualize RNA expression and provide topological information about expression patterns. SPECIAL REQUIREMENTS A. Annual Meetings of Grantees The NIDDK Program Director will convene a group consisting of the Principal Investigators of each funded grant, a NIEHS Program Director, plus invited expert consultants. Annual meetings will encourage exchange of information among the Principal Investigators. A major goal of these meetings is to facilitate progress by providing a forum that will lead to coordination, and sharing of skills, ideas, technology, data, biological reagents, and bioinformatics. Applicants must include in their proposal travel funds for the Principal Investigator and up to one other key research scientist for three 1-day meetings the first year and two 1-day meetings in subsequent years, all in Bethesda, Maryland. The Principal Investigator must include a statement indicating willingness to participate in these meetings, follow common protocols, and collaborate with other grantees. During the grant period, technologies will improve and the rate of progress and focus of work supported by the grant(s) may change. The Principal Investigator(s), in consultation with the other grantees and the NIDDK and NIEHS Program Directors, will make any necessary adjustments to accommodate the changing research environment, to remain focused on appropriate goals, to maintain excellent coordination with the other projects funded under this RFA, and to incorporate new technological advances. B. Sharing Data and Biological Materials in Human Genetic Research Timely sharing of information, materials, and technology will speed scientific discovery by permitting researchers access to sufficiently large and well-characterized resources as quickly as possible. This sharing of materials and data, including those not yet or never published, is essential to rapid progress and will help to avoid unnecessary duplication of large data collections. To ensure timely sharing of information and materials, applications should describe in detail how, when, and in what manner data, materials, and technology will be made available to the scientific community. In addition, applicants should outline plans to adequately safeguard the genetic research rights and interests of participants. A period of time will be required to verify the accuracy of data, perform initial analyses, and protect intellectual property rights to ensure that inventions, including therapeutic agents, are pursued and developed rapidly for the benefit of the public. Thus, a protected period, from the time data and materials are collected to the time they are made available to other qualified investigators, may be appropriate. The onset and duration of this period will vary, depending upon the nature of the research project. Applicants must justify the length of the proposed protected period. Applicants should discuss any pre-existing intellectual property rights, including options to for-profit research sponsors that might be associated with the clones, sequences, and experimental results that may be generated. Where appropriate, grantees may work with the private sector to make unique resources available to the larger biomedical research community at a reasonable cost. Applicants may request funds to defray the costs of sharing materials or submitting data, with adequate justification. 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 subpopulations 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 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html 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: https://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit by March 21, 2000, a letter of intent. Include a descriptive title of the proposed research; the name, postal and email addresses, and telephone number of the Principal Investigator; the names of other key personnel and participating institutions; and the number and title of this RFA. 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 NIH staff to estimate the potential review workload and avoid conflict of interest in the review. Send the letter of intent to: Chief, Review Branch Division of Extramural Activities, NIDDK Natcher Building, Room 6AS-37F 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms 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: GrantsInfo@nih.gov, and at https://grants.nih.gov/grants/funding/phs398/phs398.html. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS All grant applications responding to this RFA must follow the format for modular grants and will request direct costs in $25,000 modules, up to a total direct cost request of $350,000 per year ($100,000 for R21s). The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $350,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Indirect costs for subcontracts are included in the total costs for the application. The subcontract costs should not be in modular form but should be rounded to the nearest $1,000. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers to assess each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page. - List position(s) and any honors. - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations. o CHECKLIST: Complete and submit this page with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o Provide the name and phone number of the individual to contact concerning fiscal and administrative issues should additional information be necessary following the initial review. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could delay processing of the application such that it may not reach the review committee in time for review. In addition, type the RFA title and number on line 2 of the face page of the application form and mark the YES box. 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, send two additional copies of the application to: Chief, Review Branch Division of Extramural Activities, NIDDK Room 653, 6707 Democracy Blvd, MSC 5452 Bethesda, MD 20892-5452 Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revisions 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 previously 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 and NIEHS. 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 review criteria stated below. 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 appropriate National 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. 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? 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? Are the proposed target cells important in clinical disease or development? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Do they utilize state-of-the-art technology? Is the necessary technical and analytical expertise available? Does the applicant acknowledge potential problems and {offer/suggest} alternative tactics? Is the approach broad and diverse enough to find and characterize something new and innovative? (3) Innovation: Does the project employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Will the resultant cell-specific reagents advance understanding of developmental disorders and clinical diseases? It is understood that some of the projects might be more descriptive than hypothesis driven. However, has the investigator adequately justified this approach and adequately described and limited the descriptive portion leading to the development of a testable hypothesis? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the proposed work appropriate to the experience of the principal investigator and other researchers (if any)? Has the investigator submitted a statement agreeing to participate and collaborate with the other grantees? (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? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: 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 Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources. o Does the applicant state a willingness to work with other grantees to develop the best possible set of tools for studying prostate and genitourinary development? Is the applicant willing to share protocols and technology with the research public? Schedule Letter of Intent Receipt Date: March 21, 2000 Application Receipt Date: April 21, 2000 Peer Review Date: June/July 2000 Council Review: September 20-21, 2000 Earliest Anticipated Start Date: September 29, 2000 AWARD CRITERIA Criteria for award decisions include: o Scientific merit as determined by peer review; o Availability of funds; o Programmatic priorities that include ensuring a diverse representation of targeted cells of NIDDK and NIEHS interest and willingness to work with other institutions to minimize overlap between grantees; and o Recommendations of NIDDK and NIEHS Advisory Councils. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Robert A. Star, M.D. Kidney, Urologic and Hematologic Diseases NIDDK Room 9A-35 31 Center Drive MSC 2560 Bethesda, MD 20892-2560 Telephone: (301) 594-7715 FAX: (301) 480-3510 E-mail: StarR@extra.niddk.nih.gov Leroy M. Nyberg, Jr., Ph.D., M.D. Kidney, Urologic and Hematologic Diseases NIDDK 45/6AS-13G 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 E-mail: NybergL@extra.niddk.nih.gov Michael E. McClure, Ph.D. Division of Extramural Research and Training Organs and Systems Toxicology Branch, NIEHS111 T.W. Alexander Drive P.O. BOX 12233, Mail Drop EC-23 Research Triangle Park, NC 27709 Telephone: (919) 541-5327 FAX: (919) 541-5064 E-mail: mm461n@nih.gov Direct inquiries regarding fiscal matters to: Trude Hilliard Division of Extramural Activities NIDDK 45/6AN-44B 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8859 E-mail: HilliardT@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.849 and 93.113. Awards are 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 NIH 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 NIH mission to protect and advance the physical and mental health of the American people.
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