FUNCTIONAL GENOMICS OF THE DEVELOPING ENDOCRINE PANCREAS Release Date: December 4, 1998 RFA: DK-99-007 P.T. National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: February 10, 1999 Application Receipt Date: March 10, 1999 PURPOSE The development of type 1 diabetes is characterized by a progressive autoimmune destruction of pancreatic beta cells resulting in loss of insulin production. Replacement of beta cell function through transplantation or regeneration of beta cells could provide a major breakthrough in the treatment of diabetes. However, the lack of sufficient tissue is a major obstacle to the widespread use of transplantation and an incomplete understanding of the development and differentiation of the pancreatic islet reduces the likelihood of successful regeneration of beta cells either in vitro or in vivo. To accelerate progress toward identification of pleuripotential stem cells and factors which regulate development and differentiation of beta cells the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites investigator-initiated Resource-Related Research Projects (R24) to establish a pilot functional genomics resource in diabetes. This grant award mechanism would support production and sequencing of expression cDNA libraries based on multiple stages of pancreatic development. In addition, this resource would provide bioinformatics links to existing NIH-supported genomics databases and make pancreatic cDNA libraries available as microarrays to be used by researchers for gene discovery and functional investigations in both normal and diabetic pancreas. 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 RFA, Functional Genomics of the Developing Endocrine Pancreas, 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 Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone: 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and nonprofit organizations, public or private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Foreign institutions are not eligible for resource-related research project (R24) grants. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Support of this program will be through the NIH grant-in-aid resource-related research project grant (R24) award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement. This RFA is a one-time solicitation. However, if there is sufficient continuing program need, NIDDK will invite recipients of awards under this RFA to submit competing continuation applications for review as described in REVIEW CONSIDERATIONS. The total requested project period for an application submitted in response to this RFA may not exceed 3 years. The maximum dollar request is limited to $500,000 in direct costs for the initial budget period and $1.5 million in direct costs for the entire project period exclusive of equipment. The anticipated award date is September 30, 1999. FUNDS AVAILABLE For FY 1999, $1.5M will be committed to fund applications submitted in response to this RFA. It is anticipated that one to two awards will be made; however, this funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. Proposed funding levels are subject to change due to budgetary, administrative and/or scientific considerations, and are dependent upon the receipt of a sufficient number of applications of high scientific merit. It is expected that major equipment costs will be incorporated in the first year budget, and that subsequent year budgets should be related to the anticipated level of library production and sequencing. Although this program is provided for in the financial plans of the NIDDK, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background On September 4-5, 1997, the NIH sponsored a conference, "Diabetes Mellitus: Challenges and Opportunities." focused on scientific opportunities and directions that a broad interdisciplinary approach could bring to diabetes research. Led by invited, internationally recognized experts in diabetes research, this conference involved all NIH institutes having a scientific interest in diabetes. A primary recommendation of that group was the application of cDNA microarray technology to the problem of type 1 diabetes. Over time a general outline of the morphological events involved in the development of the endocrine pancreas has emerged. Signals from adjacent tissues, including the notochord and the mesenchyme, play an important role in pancreatic islet development and key mediators of these inductive signals are now being elucidated. Recent results have increased our understanding of how the genes required for normal function of the beta cell are activated. This work has included the detailed knowledge of insulin and glucokinase gene regulation and the insights into the role that a series of tissue-specific transcriptional activators, the HNFs, play in the regulation of genes involved in glucose sensing. Additional findings have identified transcription factor genes involved in the formation and the maturation of the pancreas and islets. These factors include IPF1, which is required for formation of the entire pancreas, and isl1, neuroD1/BETA2 and pax and nkx genes, which are involved in the formation, expansion and maturation of islet cells. Finally, growth factors have been identified that control the growth and regeneration of islet cells. These results form the foundation for expanding research efforts to understand development of the endocrine pancreas and offer the potential to stimulate regrowth of beta cells in patients with diabetes. However, a number of gaps still remain in our understanding of pancreatic development. The developmental triggers which establish the pancreatic beta cell lineage and the inductive signals which control progression to differentiated beta cells have not been elucidated. Recent advances in DNA technologies including microarray construction, sequencing speed and fidelity, and library construction increase the likelihood of discovering many of the genes that regulate development of the endocrine pancreas. In addition, the identification of beta cell specific genes should provide a powerful tool to look at altered function during the progression of type 1 diabetes. The National Cancer Institute (NCI) has established the Cancer Genome Anatomy Project to accelerate the pace of discovery of genes involved tumor progression and to attempt to harness the vast wealth of sequence data emanating from the Human Genome Project. CGAP has become a national network of labs orchestrated by NCI staff to both discover new cancer genes and elucidate characteristic patterns of gene expression in normal and malignant tissues which potentially could be useful in diagnosis and treatment of many cancers. The bioinformatics system which has been developed for CGAP ensures that all of the data generated by this project is available to researchers worldwide soon after it is generated in the laboratory. One logical extension of this project, that is, the development of tools which can use this data in laboratory investigations or clinical diagnosis is relatively undeveloped. The current RFA is designed to stimulate investigations into the application of microarray and detection technologies to the problem of diabetes through generation of pancreatic cDNA libraries, sequencing, and construction of microarrays to be used by the general research community. Objectives and Scope This RFA is intended to support the cost-effective generation of arrays of genes involved in development and differentiation of the mammalian endocrine pancreas. Since many of these factors may be expressed at very low levels at key stages in development, strategies should be proposed to increase the representation of low abundance transcripts in the cDNA libraries and to decrease the redundant sequencing of overrepresented or known genes. Applicants may also propose selection strategies which can be used to determine key regulatory factors in beta cell development and to develop strategies for regeneration either in vivo or in vitro of beta cells as a potential therapy for type 1 diabetes. Other tissues relevant to diabetes may be included in the proposal, but cannot supplant the primary objective to focus on developing pancreas. Experiments focused on determination of the validity and reliability of pancreatic gene microarrays as well as their utility in diabetes research may be proposed as well. A major objective of this RFA is to disseminate both sequence data and research reagents to the research community as rapidly as possible. Therefore, applicants should exploit existing microarray technologies, which are readily available to the research community, or propose alternative technologies including plans to make them widely available to researchers. A schedule for rapid disposition of sequences into public databases such as GenBank should be proposed. A strategy for developing and maintaining a distinct bioinformatics system for diabetes related genes may be proposed as an additional resource for researchers. SPECIAL REQUIREMENTS Data and Resource Dissemination The sharing of materials and data in a timely manner has been an essential element in the rapid progress that has been made in genome research. Public Health Service (PHS) policy requires that investigators make the results and accomplishments of funded activities publicly available. The advisors to the NIH and the DOE genome programs have encouraged more rapid sharing, and this has become the norm in the genome community. NIDDK encourages applicants who respond to this RFA to develop and propose specific plans for sharing data and materials generated through the resource-related research project grant. It is anticipated that data obtained, upon sequence validation should be placed in a public database. For example, the National Center for Biotechnology Information, National Library of Medicine (NCBI, NLM) has already in place a database that contains organized sequence data from libraries produced through the Cancer Genome Anatomy Project. Applicants need to describe plans for dissemination of their sequence data, and the compatibility of their database with other public databases. Where appropriate, awardees may work with the private sector in making the arrayed libraries available to the larger biomedical research community at a reasonable cost. The plans proposed for sharing and data release will be reviewed for adequacy by reviewers as well as NIDDK staff prior to award and will be considered as a criterion for award. Funds to defray the costs of submitting data and distribution of reagents may be included in the application. Such requests must be adequately justified. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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 LETTER OF INTENT Prospective applicants are asked to submit, by February 10, 1999, a letter of intent that includes a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; 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 NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F, 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, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov or electronically at https://grants.nih.gov/grants/forms.htm. 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 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. Submit a signed, typewritten original of the application, including the Checklist, plus 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 time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F, MSC 6600 Bethesda, MD 20892-6600 Applications must be received by March 10, 1999. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS 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 NIDDK in accordance with NIH peer review procedures. 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 of the RFA. 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 will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases 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. o 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? o 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? o Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o 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? o Appropriateness of the proposed budget and duration in relation to the proposed research. 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 initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. Additional Review Criteria Specific for this RFA: o The feasibility and merit of the strategy for increasing representation of rare transcripts. o Plans to distribute forthcoming resources in a timely manner, preferably with track-record of willingness to release data and reagents. AWARD CRITERIA The anticipated date of award is September 30, 1999. The factors that will be used to make award decisions include: o scientific and technical merit as determined by peer review o provision for rapid dissemination of results to the research community, o availability of funds o programmatic priorities 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: Philip F. Smith, Ph.D. Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8816 FAX: (301) 480-3503 Email: ps56z@nih.gov Direct inquiries regarding fiscal and administrative matters to: Kieran Kelley Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-0417 FAX: (301) 480-3504 Email: kk27g@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 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. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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