$$XID RFA DK9214 DK-92-14 P1O1 ***************************************** GENES RESPONSIBLE FOR INSULIN DEPENDENT DIABETES MELLITUS NIH GUIDE, Volume 21, Number 10, March 13, 1992 RFA: DK-92-14 P.T. 34; K.W. 0755020, 0740075, 0775020, 0710070 National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: June 18, 1992 Application Receipt Date: July 22, 1992 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites investigator-initiated research grant applications to identify specific genes responsible for insulin dependent diabetes mellitus (IDDM) in humans. It is anticipated that this identification will require an interdisciplinary approach to develop and utilize strategies that will elucidate genes responsible for IDDM using appropriate familial pedigrees. This solicitation intends to support the efforts of several independent investigators, working in a collaborative manner to acquire sufficient genetic material, achieve the mutual objectives, and efficiently integrate and analyze the results obtained. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Genes Responsible for Insulin Dependent Diabetes Mellitus, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications for research grants may be made by public and private, foreign and domestic, for-profit and non-profit organizations, such as universities, colleges, hospitals and laboratories, units of State and local governments, and authorized units of the Federal Government. Women and minority investigators are encouraged to apply. MECHANISM OF SUPPORT The mechanism of support for this program will be the research project grant (R01). The regulations (Code of Federal Regulation, Title 42, Part 52 and, as applicable to State and local governments, Title 45, Part 74) and policies that govern the research grant programs of the National Institutes of Health will prevail. This RFA is a one-time solicitation. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date will be April 1, 1993. 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 NIH peer review procedures. FUNDS AVAILABLE Up to $1 million for first-year expenses, and additional approved expenses for up to five years, will be committed by the NIDDK to fund applications submitted in response to this RFA. The NIDDK plans to make approximately five awards in FY 1993 contingent on the receipt of highly meritorious applications in response to this solicitation. In order to adhere to prudent principles of cost-containment, requested direct costs may not exceed $160,000 for any single application. With respect to post-award administration, the current policies and requirements that govern the research grant programs of the NIH will prevail. The award of grants pursuant to this RFA is contingent on the availability of funds for this purpose. RESEARCH OBJECTIVES Background The term "diabetes" encompasses a number of different diseases and hence a number of different genes may be involved. Because of the potential for complex interplay between several genes, novel approaches may be necessary to ascertain the genes involved in the etiology of diabetes. The NIDDK recognizes this area as a high priority for research and has taken steps to stimulate research in genetics and molecular biology. In addition, the National Diabetes Advisory Board, in its "Long-Range Plan to Combat Diabetes, 1987," made several recommendations to the NIDDK directed at increasing progress in this area including increasing the emphasis on interdisciplinary research collaboration. In 1990, the NIDDK convened a scientific workshop to address opportunities in the search for the diabetes genes. The participants analyzed the current state of knowledge and endorsed a multifaceted and concerted effort to discover the genetic basis of diabetes and its complications. The last decade has witnessed an expansion in knowledge and scientific methods allowing the isolation of genes responsible for a few but growing number of severe human diseases such as Duchenne muscular dystrophy and Huntington's disease. Most recently, a five-year effort has culminated in the cloning and sequencing of the gene responsible for cystic fibrosis. This achievement has had a dramatic effect on research into the cause and cure for cystic fibrosis. Similar scientific approaches are being directed toward the search for the diabetes genes. There has already been progress in the search for the diabetes genes. Within the last three years, a discovery has uncovered a diabetes susceptibility gene in IDDM, which affects between 500,000 and 750,000 children and young people in the United States. This gene appears to be necessary, but not completely sufficient, to cause the disease. In animal models there is a suggestion that additional genes are involved, but as yet, no other gene has been identified in humans. There is a need to search for these other contributing genes in IDDM. The clinical manifestations of IDDM are the culmination of a destructive immune process that has gone on silently for years. By the time the patient's sickness occurs, it is generally too late to prevent or reverse the damage. Therefore, it is important to find markers for the process at an earlier stage. These markers can take the form of genetic-susceptibility markers, identifying the presence of specific genetic loci, and/or immunological markers, identifying an early manifestation of the autoimmune process. While this RFA is designed to identify genes associated with IDDM, the NIDDK anticipates a future RFA specifically focusing efforts on the identification of genes involved with non-insulin dependent diabetes mellitus. Scope The objective of this RFA is to stimulate investigator-initiated research grant applications designed to develop and utilize new molecular genetic strategies to provide a better understanding of the major human genes involved in IDDM. To achieve this objective, appropriate family pedigrees may have to be collected as a prerequisite for the identification or for the verification of specific gene involvement. Since a large number of families may need to be recruited, accumulation of these families must be included within the framework of the proposed research plan. Utilization of existing sources of genetic material collaboration among researchers is encouraged. The degree of this collaboration may range from sharing appropriate family pedigrees or genetic material to devising a joint plan that divides the studies among the collaborating laboratories and specifies a central laboratory responsible for such activities as coordinating acquisition of genetic material, data analysis, and manuscript preparation. It is anticipated that these results will elucidate mechanisms involved in disease onset and thus enable the development of specific intervention therapies and the identification of individuals at risk for the development of IDDM. Relevant research topics listed below are examples and should not be construed as required or limiting. Applications responsive to this solicitation would include: o development of gene mapping strategies for the specific identification and localization of genes for IDDM o utilization of subtractive hybridization techniques to identify pathophysiologic processes in IDDM o employment of highly informative polymorphic markers, such as variable number repeat polymorphisms or microsatellite markers, to evaluate relevant family pedigrees Applications must propose the testing of a hypothesis rather than the establishment of, for example, a genetic resource. SPECIAL REQUIREMENTS Upon initiation of this program, the NIDDK will sponsor periodic meetings to encourage exchange of information among investigators, foster collaborative efforts between program grantees, and identify resources that would enhance the productivity of grantees. For this purpose, requests for travel funds for a one-day meeting each year, probably to be held in Chicago, IL, should be included in the budget section of the application. Applicants should also include a statement in the application indicating a willingness to participate in such meetings and to cooperate with other researchers in the exchange of data, materials, and ideas. In the case of a collaboration, inclusion of an agreement of participants to adhere to group decisions on data ownership and publication rights may be advantageous. If several independent investigators have entered into a collaboration, it is necessary to identify a specific investigator who will act as the group coordinator. All applications submitted as components of a collaboration MUST cite the group coordinator on page 2 under "Key Personnel Engaged on Project" of the form PHS 398. Direct costs related to this coordinating activity may not exceed $50,000 per year. These funds would be in addition to the funds (up to $160,000) related to the research activities proposed by the coordinating institution. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDIES NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in Section 2, 1-4 of the Research Plan and summarized in Section 2, E, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventative strategies), diagnosis, or treatment or diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Potential applicants are strongly encouraged to submit a letter of intent by June 18, 1992. The letter of intent is to include the names of the Principal Investigator/program director and principal collaborators, descriptive title of the potential application, and identification of the organization(s) involved. The letter of intent is to be sent to the Chief, Review Branch, NIDDK, at the address noted below under "Application Procedures." Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NIDDK staff to estimate the potential review workload and to avoid conflict of interest in the review. APPLICATION PROCEDURES Applications are to be submitted on form PHS 398 (rev. 9/91) which is available from an applicant institution's Office of Sponsored Research and from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301-496-7441. Use the conventional format for research project grant applications. To identify the application as a response to this RFA check "yes" on item two of page one of the application and enter the title "Genes Responsible for Diabetes" and the RFA number DK-92-14. As indicated under "Mechanism of Support," if a collaboration of individual investigators is planned, it is necessary to identify one of the investigators as the group coordinator and to cite this individual in all applications on page 2 of the form PHS 398. The RFA label included in the PHS 398 application package must be affixed to the face page to assist in the processing of the application. Failure to use this label could result in the delayed processing of the application such that it may not reach the review committee in time for review. Applications must be received by July 22, 1992. If an application is received after that date, it will be returned to the applicant. Applicants who have entered into a collaboration may submit the applications individually with a cover letter noting their involvement and listing the other members of the collaboration. The original, including the Checklist, and three copies of the application must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must be sent under separate cover to: Review Branch National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 605 5333 Westbard Avenue Bethesda, MD 20892 The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG 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 by NIH staff for completeness and responsiveness. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, as determined by NIDDK staff, the applicant will be contacted to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. In the event that the number of applications is large compared to the number of awards to be made, the NIH may conduct a preliminary scientific peer review (triage) to eliminate those applications that are clearly not competitive. The NIH will administratively withdraw from competition those applications judged to be noncompetitive and notify the applicant and institutional business official. Competitive applications will be assigned to a special peer review group convened by the NIDDK. Following review by the initial review group, the applications will be considered by the National Diabetes and Digestive and Kidney Diseases Advisory Council in February 1993. Applications in response to this solicitation will be reviewed using the usual NIH peer review procedures. The factors to be considered in the evaluation of scientific merit of each application will be those used in the review of traditional research project grant applications, including the novelty, originality, and feasibility of the approach; the training, experience, and research competence of the investigator(s); the adequacy of the experimental design; the suitability of the facilities; the appropriateness of the requested budget to the work proposed; and the adherence, whenever appropriate, to NIH guidelines concerning clinical research involving minorities and women. For those applications that propose collaborative efforts between several applicants, additional factors to be considered during the review would include the efficacy of the collaboration, the commitment of the participants to the collaboration, the design and responsibilities of the coordinating center and the cost effectiveness of the collaborative effort. AWARD CRITERIA The anticipated date of award is April 1, 1993. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Scientific interrelationships among the proposed projects. 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 to: Joan T. Harmon, Ph.D. Executive Director, Diabetes Research Program Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 622 Bethesda, MD 20892 Telephone: (301) 496-7731 Direct inquiries regarding fiscal matters to: Betty E. Bailey Grants Management Specialist Grants Management Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 649 Bethesda, MD 20892 Telephone: (301) 496-7467 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847, Diabetes, Endocrinology and Metabolism Research. 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 PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review.