DEVELOPMENT OF THE ENDOCRINE PANCREAS Release Date: December 1, 1999 PA NUMBER: PAS-00-015 National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Child Health and Human Development THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE This program announcement is intended to stimulate the application of advances in developmental biology, specifically in developmental genetics, embryology, and stem cell biology, to study pancreatic development. Collaborative efforts that link expertise in basic developmental biology or stem cell biology and diabetes are strongly encouraged. It is anticipated that this research will ultimately lead to a better understanding of the pathways required for the development and regeneration of the endocrine pancreas, both in vivo and in vitro. This PA, with set-asides of funds in FY 2000-2002, is intended to intensify investigator-initiated research, to attract new investigators to the field, and to encourage interdisciplinary approaches to research in this area. 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 PA, Development of the Endocrine Pancreas, is related to the priority area of Diabetes. 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 PA will use the National Institutes of Health (NIH) research project grant (R01) and Exploratory/Developmental Research Grant (R21) award mechanisms. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to (1) provide initial support for new investigators, (2) allow exploration of possible innovative new directions for established investigators, and (3) stimulate investigators from other areas to limit their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $100,000 direct costs per year and are limited to two years. These R21 grants will not be renewable, continuation of projects developed under this program will be through the regular research grant (R01) program. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an R01 application submitted in response to this PA may not exceed 5 years. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE For FY 2000, $1.5 million will be set aside to fund competing applications submitted in response to this PA. For FY 2001 and 2002, $2.0 million will be set aside to fund competing applications in each year. However, these funding levels are dependent upon the receipt of a sufficient number of applications of high scientific merit. The award of grants pursuant to this PA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Processes fundamental to the development of all organ systems include germ layer specification, cell fate determination, pattern formation, proliferation, and differentiation. In general, the activation of a specific developmental pathway is initiated by an extracellular signal. Signaling molecules that are utilized during development are very diverse and include members of the transforming growth factor superfamily (TGFs, including bone morphogenetic proteins), the epidermal growth factor family (EGFs), the fibroblast growth factor family (FGFs), the wingless family (Wnts), sonic hedgehog family (shh), Notch-like signals, and cytokines such as interleukin- 3 (IL-3). Additionally, signaling cascades can be triggered by cell-cell or cell-matrix contact (i.e., integrins). These signaling cascades culminate in the temporal and spatial expression of an array of negative and positive transcriptional regulators. Ultimately, the "readout" of these signaling events will produce a defined cellular phenotype. Applying basic knowledge of these developmental processes may lead to the rational design of protocols to regenerate key endocrine tissues devastated by diseases like diabetes mellitus, such as the endocrine pancreas. Preliminary studies on endoderm development show that inductive signals, including those of the TGF beta family, can specify endoderm, inducing endodermal-specific transcriptional determinants such as Mixer and the Sox genes. Signals produced by the notochord, the tissue adjacent to the endoderm, are thought to be responsible for determining pancreatic cell fate. Development of endocrine organs involves the "budding morphogenesis" of an epithelial layer in order to create a specific organ. The dorsal pancreatic bud expresses a number of transcriptional regulators, including Isl1, pdx1/IDX1, nkx2.2, pax 4, pax6 and HNF 3 beta. Many of these transcriptional regulators are required for proper development of the endocrine pancreas. Signals such as shh must be excluded from the developing pancreatic anlagen for proper pancreas development, while signals produced by mesenchyme are necessary for pancreatic differentiation into specified cell types. For the endocrine pancreas, this ultimately means differentiation into cell types responsible for production of insulin, glucagon, etc. TGF alpha/betas in their regulation of the extracellular matrix may be key activators in islet morphogenesis. In the last decade, studies in non-vertebrate genetic models of C. elegans and Drosophila, have provided a wealth of scientific advances in the definition of early developmental pathways. In the next decade, the emerging genetic model, zebrafish, can be exploited for dissecting events in endoderm development and morphogenesis of the pancreas. Non-genetic models such as Xenopus and chick have proven useful in identifying and characterizing novel signals and associated components of signaling pathways as well as transcriptional regulators in endoderm development and organ morphogenesis. BETA2/NeuroD, a basic helix-loop-helix transcription factor involved in pancreatic endocrine development was isolated using insulin gene regulation as a paradigm. The study of how cell- and tissue-specific gene expression in beta cell development is regulated may lead to the generation of useful animal models of diabetes (i.e. conditional knock-outs in the mouse). The combined use of non-mammalian and mammalian developmental model systems will play an important role in understanding endoderm development and, in particular, the development of the endocrine pancreas. Type 1 and type 2 diabetes result from the anatomical and functional loss of insulin-producing beta cells of the pancreas. Replacement of these cells through regeneration or transplantation could offer lifelong treatment for diabetics. However, a major problem in implementing treatment is the lack of sufficient islet cell tissue for transplantation, and a lack of understanding of whether and how beta cells regenerate. Embryonic stem cells and other tissue-specific stem cells could potentially provide a limitless source of islet cells for transplantation therapies. Despite major advances in stem cell research and in defining specific developmental pathways in neurobiology and hematopoiesis, a fundamental understanding of the developmental pathways leading to formation of differentiated cells in the endocrine pancreas is still in its infancy. Scope and Objectives Investigators with diverse scientific interests are invited to apply their expertise in basic research to enhance our fundamental understanding of development of the endocrine pancreas. Examples that illustrate areas to be considered within the intent of this solicitation are presented below. The following examples should be considered illustrative and not restrictive, and other innovative approaches are encouraged: o Developmental genetic screens for identifying mutations in endoderm that affect pancreas development. o The identification of signals, signaling pathway components, and transcriptional factors that regulate endoderm specification, dorsal pancreatic bud formation, and pancreatic cell fate determination. o The role of cell-cell interactions, differential cell adhesion and cell motility in morphogenesis of the pancreas. o The role of extracellular matrix in islet cell morphogenesis. o Molecular markers for defining all stages of pancreas development, including cell-specific markers of stem/progenitor cells of the endocrine pancreas. o Studies examining endocrine pancreatic cell lineage, including alpha, beta, and delta cell fate determination and differentiation. o Studies exploring the potential use of embryonic stem cells, hematopoietic, neural and other stem cells in the formation of differentiated cells of the endocrine pancreas. o Identification of growth conditions required to generate differentiated cells of the endocrine pancreas from stem/progenitor cells. o Generating or using model systems for the study of regeneration of the endocrine pancreas. 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 new 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 http://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: http://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. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, or 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- 435-0714, email: [email protected]. Applicants planning to submit an investigator-initiated new (type 1) competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact NIDDK or NICHD 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 Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.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 Modular R01 Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) R21 applications will request 1 or 2 modules of $25,000. 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 $250,000) 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 http://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. 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 in the assessment of 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: http://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: This page should be completed and submitted 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 The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The program announcement 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 the signed, original, single-sided application, including the Checklist, along with five signed photocopies and five collated sets of appendix materials 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) The Center for Scientific Review (CSR) will not accept any application in response to this PA 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 Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second-level review by the appropriate national advisory council or board. 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, reviewer will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 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? 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 which are not readily available in the United States or which provide augmentation of existing U.S. resources. AWARD CRITERIA Applications will compete for available funds within the annual set-aside mentioned under FUNDS AVAILABLE. Beyond the limits of the set-aside applications will compete with all other recommended applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases. 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 Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Sheryl M. Sato, Ph.D. Division of Diabetes, Endocrinology, and Metabolism NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8811 FAX: (301) 480-3503 E-mail: [email protected] Gilman Grave, M.D. Center for Research for Mothers and Children NICHD 6100 Executive Blvd., Room 4B11 Bethesda, MD 20892-7510 Telephone: (301) 496-5593 FAX?301) 480-9791 E-mail: [email protected] Direct inquiries regarding fiscal and administrative matters to: Ephraim Johnson Division of Extramural Activities NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8868 E. Douglas Shawver Grants Management Branch NICHD 6100 Executive Blvd., Room 8A17 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 FAX?301) 402-0915 E-mail: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.847 and 93.865. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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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