and Human Services (HHS)
EXPIRED
BETA CELL BIOLOGY CONSORTIUM Release Date: October 11, 2000 RFA: DK-01-014 National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: March 16, 2001 Application Receipt Date: April 17, 2001 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is seeking applications to establish a Beta Cell Biology Consortium for the purpose of intensifying investigator-initiated research, attracting new investigators into the field, encouraging interdisciplinary approaches to research in this area, fostering the application of basic research to generate new research tools and approaches for the diagnosis, treatment, and cure of diabetes, and establishing a comprehensive database for the beta cell. Through the Consortium, individual Beta Cell Biology Programs will have access to information, resources, technologies, expertise, and reagents that are beyond the scope of any single research effort. This RFA is a direct response to recommendations of the Congressionally-established Diabetes Research Working Group (http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm) that developed a strategic plan for research in diabetes. Two of the extraordinary research opportunities recommended by the plan were to increase basic research on the control and regulation of islet cell differentiation, growth and development and to create interdisciplinary centers for Beta Cell Biology to expand current efforts and bring new investigators into the field . An NIDDK/Juvenile Diabetes Foundation (JDF) workshop entitled, Imaging the Pancreatic Beta Cell held in April, 1999, further recommended the development of imaging techniques that could be used to assess beta cell mass in the pancreas. A recent RFA entitled, Imaging Pancreatic Beta Cell Mass, Function, or Inflammation addressed recommendations from that workshop, as does this solicitation. In response to the DRWG report, a NIDDK/American Diabetes Association (ADA)/JDF sponsored workshop, Stem Cells and Pancreatic Development was held in April, 2000. Workshop participants recommended the development of specific reagents, assays and animal models, and increased collaboration among stem cell biologists, developmental biologists, and diabetes investigators to achieve the goal of developing a cellular replacement therapy for diabetes. Each program will be in the general form of a program project, composed of several projects and one or more cores relating to the overall theme of the program. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and 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 The administrative and funding instrument to be used for these awards will be the program project cooperative agreement (U19). The cooperative agreement is an assistance mechanism in which substantial NIDDK scientific and programmatic involvement is anticipated during the performance of the activity. Under the cooperative agreement, the NIDDK’s purpose is to support and encourage the recipient’s activities by working jointly with the awardees in a partnership role, but not to assume direction, prime responsibility, or dominance. Details of the responsibilities, relationships, and governance of a study funded under a cooperative agreement(s) are discussed later in this document under the sections titled Objectives and Scope , Special Requirements , and Terms and Conditions of Award . The total project period for applications submitted in response to this RFA may not exceed five years. The anticipated award date is September, 2001. At this time, the NIDDK has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The NIDDK plans to commit up to $7.25 million in FY 2001 to fund approximately five new awards for Beta Cell Biology Programs. It is anticipated that an additional $500,000 in direct costs/year will be used to establish the Bioinformatics Coordinating Center in FY 2002. An applicant may request a project period of up to five years. The award for each Beta Cell Biology Program will be limited to $1 million in direct costs/year. The number of awards to be made is dependent on the receipt of a sufficient number of applications of high scientific merit and on the availability of funds. Although this program is provided for in the financial plans of the NIDDK, 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 Background The beta cell of the endocrine pancreas plays a critical role in the pathogenesis of both type 1 and type 2 diabetes. Thus, having a comprehensive understanding of the molecular basis of beta cell development and function should generate new research tools and provide critical insights into the prevention and treatment of diabetes. In FY 1999, the NIH initiated a project entitled Functional Genomics of the Developing Pancreas. Currently, cooperative agreements support the efforts of a consortium of researchers to identify all of the genes expressed over the lifespan of the beta cell in mice and humans. This consortium ultimately will identify novel genes that may reveal key regulatory mechanisms in controlling the differentiation of beta cells and provide information useful in developing strategies in beta cell replacement and the modulation of autoimmune beta cell destruction. The ongoing program will develop comprehensive microarrays of genes expressed in the beta cell allowing investigations of global gene expression in islets from mouse models of diabetes and in islets from humans. The Endocrine Pancreas Consortium Database, www.cbil.upenn.edu/EPConDB, allows investigators access to these data and will promote research on the differentiation and regeneration of beta cells. One of the goals of the current RFA is to build upon the foundation of the ongoing Functional Genomics of the Developing Pancreas Consortium through the initiation of a series of complementary projects to further understand the function of the beta cell, and to generate reagents and assays needed for the development of novel cellular therapies for diabetes. In addition to the Functional Genomics of the Developing Pancreas Consortium, major scientific advances and technological breakthroughs in basic disciplines such as developmental biology, stem cell biology, mouse genetics, imaging, bioengineering, and bioinformatics demand that a multifaceted, interdisciplinary, and coordinated, collaborative approach on several fronts be utilized to generate key reagents, assays and new strategies for the diagnosis, treatment and prevention of type 1 and type 2 diabetes. Objectives and Scope The NIDDK will fund as components of the Beta Cell Biology Consortium approximately five Beta Cell Biology Program applications, each supporting a multidisciplinary team. A Beta Cell Biology Program could consist of several collaborating investigators representing one or more institutions. Each program, consisting of at least 3 projects and one or more cores, must address at least two of the six targeted scientific areas described below. Each program must include a plan that addresses the need for data coordination within the Consortium. 1. Beta Cell Development A goal of this RFA is to attract expertise in developmental genetics, embryology, stem cell biology, and diabetes and to stimulate collaborative interdisciplinary approaches to the study of beta cell development. It is anticipated that scientific advances in these areas will ultimately lead to an understanding of the developmental pathways required to produce a fully functioning pancreatic islet and insight into the mechanisms underlying regeneration of beta cells in the pancreas. Areas of emphasis may include, but are not restricted to: o Characterization of molecular markers for defining all stages of pancreas development, including cell-specific markers that would delineate stem/progenitor cells of the pancreas. o Investigation of islet cell lineage, cell fate determination, and differentiation. o Exploration of the potential use of human or mouse embryonic stem cells, fetal or adult human hematopoietic, neural, and other tissue- specific stem cells in the formation of pancreatic beta cells. o Identification of key signals, signaling pathway components, and transcription factors that regulate beta cell fate determination. o Elucidation of mechanisms underlying the regeneration of pancreatic beta cells. o Investigation of the role of cell-cell interactions, extracellular matrix components, differential cell adhesion, and cell motility in morphogenesis of the endocrine pancreas. 2. Prospective Identification and Purification of Pancreatic Stem/Progenitor Cells Type 1 and type 2 diabetes result from the anatomical or functional loss of insulin-producing beta cells of the pancreas. Replacement of these cells through transplantation could offer lifelong treatment for diabetes. A major obstacle in implementing treatment is the lack of sufficient islet cell tissue for transplantation. Tissue-specific stem cells potentially could provide a limitless source of islet cells for transplantation therapies. Generating reagents such as antibodies to stem cell surface markers would facilitate development of a cellular therapy for diabetes involving stem cells. In general, stem cell populations are rare and represent only a small fraction of the total number of cells in a developing or regenerating tissue, and thus need to be greatly enriched. Methodologies using monoclonal antibodies to cell surface markers have been used to enrich and purify hematopoietic and neural stem cells. For example, common myeloid, as well as common lymphoid, progenitors from mouse or human have been isolated prospectively, and then purified and characterized using antibodies to cell-surface markers and flow cytometry. Despite recent advances in understanding some of the transcriptional regulators important in pancreatic development, major obstacles for isolating a stem/progenitor cell population from the pancreas exist, including the lack of appropriate cell surface markers and only a cursory understanding of the lineage of beta cells during regeneration and development. Overcoming these obstacles would greatly facilitate efforts to isolate, purify, and characterize stem/progenitor cells of the endocrine pancreas. One objective of this solicitation is to encourage the development of antibodies to cell surface markers specific for stem/progenitor cells of the pancreas and the use of these antibodies to isolate and purify these cells using flow cytometry. Examples of approaches include but are not limited to: o Isolation of appropriate mouse or human tissue for generating cell surface antibodies. Sources may include: - Dissected mouse or human fetal tissue (developing foregut or pancreatic buds) - Purified endodermal precursors derived from adult or fetal liver, gut, lung, or other endodermal-derived tissue - Stem/progenitor cells isolated from the regenerating pancreas - Isolated pancreatic precursor cells from genetically defined mouse models (for example, enrichment of cells from transgenic lines in which green fluorescent protein (GFP) is driven by a pancreas-specific, developmentally regulated promoter) o Utilization of the database developed by the Functional Genomics of the Developing Pancreas Consortium to identify potential cell surface markers specific to stem/progenitors of the developing pancreas from which antibodies could be generated. 3. Development of Clonogenic Assays for Evaluating Potential Stem Cells Although there are several existing diabetic animal models that might be appropriate for a clonogenic assay, this RFA will support the development of new transgenic mouse models, created through genetic engineering, in which the complete destruction of pancreatic beta cells has been induced in adults. These animal models then could be used in reconstitution assays to determine the differentiation potential of pancreatic stem/progenitor cells. Stem cells are capable of self-renewal and can give rise to multiple differentiated lineages. To characterize stem/multipotential progenitor cells, it is necessary to have quantitative assays (both in vitro and in vivo) in which to assess the ability of these cells to: (1) give rise to multiple lineages, (2) self-renew, and (3) reconstitute a cellular compartment. This RFA will support the development of in vitro clonogenic assays for assessing the potential of stem cells to become functioning beta cells. This RFA will also support the development of quantitative clonogenic in vivo assays, similar to those used to characterize hematopoietic and neural stem cells. For example, in the hematopoietic system, lethally irradiated congenic animals, in which the cells of the bone marrow have been eliminated, have been used in reconstitution assays to determine the differentiation potential of common lymphoid or myeloid progenitors. In an in vivo clonogenic assay, true pancreatic stem cells would be transferred or transplanted to a diabetic host and have the ability to reconstitute all pancreatic cell lineages. 4. Evaluation of Pancreatic Islets for Transplantation This RFA will support research to develop methods, such as the utilization of DNA array technology, for assessing the quality, purity, and viability of pancreatic islets isolated for transplantation as therapy for type 1 diabetes. Presently there are no accurate predictors of which islet preparations will survive upon transplantation. Such assays would be useful for comparison of methods of islet isolation and for development of improved approaches to islet isolation. Examples of approaches include but are not limited to: o Expression Arrays o Metabolic Markers o Antibodies to Surface Markers o Imaging Methods 5. Functional Imaging of the Beta Cell A number of new therapeutic approaches may hold promise to prevent or delay immune destruction of beta cells in people at risk for type 1 diabetes to foster regeneration or replacement of beta cells or to preserve residual beta cell function in patients with new onset type 1 diabetes. Studies to validate these proposed therapies would be greatly facilitated by the ability to image the pancreatic beta cell in patients, and detect changes in cell number, cell mass, function and metabolism. Modern molecular and functional imaging techniques potentially allow small populations of cells, like the beta cell, to be visualized in vivo. Most extant techniques, using MRI, PET, ultrasound, fluorescence or absorption spectroscopy, rely on knowledge of some unique aspect of the target cell such as a specific cell surface marker. In conjunction with information from the Functional Genomics of the Developing Pancreas Consortium and objective 2 of this solicitation, it will be possible to identify cell surface markers differentially expressed in the beta cell during development, differentiation, inflammation, or apoptosis. Taking advantage of this new opportunity, this RFA is a limited extension of a previous solicitation, Imaging Pancreatic Beta Cell Mass, Function, and/or Inflammation (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-99-018.html) to develop (1) tagged antibodies to cell surface markers specific to the beta cell, (2) related imaging methodologies for imaging the beta cell, and (3) assessing cell mass and function. Because of the highly specialized nature of this work, collaborations between imaging experts, and beta cells biologists are highly encouraged. 6. Cell Culture Model of the Human Pancreatic Beta Cell Cell lines derived from insulin-producing tumors (e.g., mouse and rat insulinomas), as well as modified neuroendocrine cells (e.g., mouse AtT20 cells), have proven useful for studies of insulin secretion, however, these culture systems do not accurately reflect all of the physiology of a normal beta cell. In bioengineering approaches to a cellular therapy for diabetes, it will be essential to have a comprehensive and global understanding, at the molecular level, of the human beta cell. This RFA will support research to develop a cell culture model of the human pancreatic beta cell that will have the following salient features: (1) stably maintain its physiologic responsiveness to glucose and other secretagogues, (2) accurately reflect in vivo signaling through cell surface and nuclear receptors relevant to the regulation of insulin production and secretion, (3) maintain responsiveness to growth factors and cytokines normally active in the development and maintenance of the pancreatic beta cell, and (4) retain contact growth inhibition as in the in vivo situation. It is anticipated that these human cell lines will be an important resource not only because of their clinical implications in the development of new therapies, but their creation will allow expression profiling studies, and a comprehensive study on cellular signaling/signaling networks in the human beta cell. Data Coordination Plan As part of an Administrative Core, each BCB program application should submit plans as to the nature of a database that will be used to store, organize, analyze, or visualize data that is generated from individual projects for the purpose of disseminating information and facilitating data sharing within the consortium. Bioinformatics Coordinating Center Within the first year, the Consortium Steering Committee, working in conjunction with the Functional Genomics of the Developing Pancreas Consortium, will develop a plan for a Bioinformatics Coordinating Center that will house and operate a centralized and comprehensive public database of the pancreatic beta cell. Additional funds for a subcontract to support the Bioinformatics Coordinating Center will be provided. The Bioinformatics Coordinating Center will be responsible for implementing a plan that will include the development of a functioning relational database, development of software to enable collection and analysis of data from many different formats and other databases, curation of existing and emerging information, and the development and maintenance of web tools and a web site for the Consortium. SPECIAL REQUIREMENTS To promote the development of a collaborative program among the award recipients, principal investigators and designated Co-PIs or Senior Investigators are expected to attend the initial planning meeting and the Beta Cell Biology (BCB) Steering Committee meetings twice a year. A major goal of these meetings is to facilitate progress by providing a forum that will lead to sharing skills, ideas, technology, data, and biological reagents. At the meetings, participants will discuss quality assurance, bioinformatics, coordination, sharing, and a means of informing the community about progress made by the Consortium. During the course of the funding period, technologies will improve and the rate of progress and scope of the research may change. It is expected the Principal Investigators, in consultation with NIDDK program staff, will make 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. TERMS AND CONDITIONS OF THE AWARD These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (U19), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient"s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Program Coordinator. 1. Awardee Rights and Responsibilities o The PI will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award. o The PI will assume responsibility and accountability to the applicant organization officials and to the NIDDK for the performance and proper conduct of the research supported by the project in accordance with the terms and conditions of the award. o The PI and one Co-PI or selected senior investigator from each program will participate as permanent, voting members of the Steering Committee. o The PI will be responsible for contributing to and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee. o The PI will be responsible for close coordination and cooperation with the other components of the BCB Consortium and with the NIDDK staff. o Awardees will retain custody of, and have primary rights to, the data developed under these awards, subject to Government rights of access consistent with current HHS and NIH policies. Investigators conducting biomedical research frequently develop unique research resources. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. Principles and guidelines for recipients of NIH research grants on obtaining and disseminating biomedical research resources can be found at: http://www.ott.nih.gov/policy/rt_guide_final.html. 2. NIDDK Staff Responsibilities The NIDDK Program Coordinator will have substantial scientific- programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship for awards, as described below. The dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Program Coordinator. o The NIDDK Program Coordinator will have voting membership on the Steering Committee and, as determined by that committee, its subcommittees. o The NIDDK Program Coordinator will coordinate and facilitate the BCB Consortium programs, will attend and participate as a voting member in all meetings of the BCB Consortium Steering Committee, and will provide liaison between the Steering Committee, the BCB Consortium, and the NIDDK. o The NIDDK Program Coordinator and the NIDDK will ensure that there is an effective, Internet-based mechanism to enable electronic communication among the BCB Consortium components and with the NIDDK. o The NIDDK Program Coordinator will assist the Steering Committee in developing and drafting operating policies and procedures for dealing with recurring situations that require coordinated action. o NIDDK and NIH extramural staff with relevant scientific expertise, or who manage research grant programs that relate scientifically to the goals of the BCB Consortium, will form the NIH Beta Cell Biology Group. The Group will meet regularly to review the progress of the BCB Consortium and to advise the NIDDK Program Coordinator of scientific developments and opportunities that may enhance the achievement of the BCB Consortium goals. o The NIH Beta Cell Biology Group will collaborate with the NIDDK Program Coordinator to organize and implement the workshops and symposia recommended by the BCB Consortium Steering Committee, and to provide a liaison between the diabetes research community and the BCB consortium. o The NIDDK reserves the right to require the transfer of animals, reagents, and pertinent data that are generated as the result of participation in research supported under these awards to an eligible third party, in order to preserve the continuity of the research project. Third parties supported under these awards must be informed of this right. o The NIDDK Program Official will review the scientific progress of individual awards and review them for compliance with the operating policies and procedures developed by the Steering Committee, and may recommend withholding of support, suspension, or termination of an award for lack of scientific progress or failure to comply with them. 3. Collaborative Responsibilities Steering Committee The NIDDK Program Coordinator and the awardees that comprise the BCB Consortium will be responsible for forming a Steering Committee as defined below. An arbitration system, as detailed below, will be available to resolve disagreements between the NIDDK Program Coordinator and the members of the Steering Committee. The Steering Committee will be the main governing board of the BCB Consortium. It will identify technological impediments to success and strategies to overcome them, and decide when reagents, assays, and animal models generated within the consortium should be made available to the research community for individual investigator-initiated projects. o The Steering Committee will be composed of the PI and a Co-PI or other senior investigator from each U19 project and the NIDDK Program Coordinator. The two investigators from each U19 project and the NIDDK Program Coordinator will each have one Steering Committee vote. The chairperson, who will be someone other than the NIDDK staff member, will be selected by the Steering Committee. o The Steering Committee may, when necessary, invite additional, non- voting scientific advisors to the meetings at which research priorities and opportunities are discussed. The NIDDK reserves the right to augment the scientific expertise of the BCB Consortium when necessary. Some of the steering committee meetings and workshops will require interaction with members of the Functional Genomics of the Developing Pancreas Consortium and the planned Diabetes Genome Anatomy Project. o There will be two Steering Committee meetings annually, one in July and the other in October, both in the Washington, DC area. o The first meeting of the BCB Consortium will be a Planning Meeting, which will take place in the Washington, DC area very shortly after award of the U19 awards. At the Planning Meeting, the Steering Committee will be formed and will select a chairperson from among the members who represent the U19 awardees. At the Planning Meeting, the Steering Committee must: (a) draft a charter to detail policies and procedures, a process for monitoring compliance with the policies and procedures, and a process for recommending that the NIDDK Program Coordinator act on evidence of non-compliance of any Consortium component with Steering Committee policies, (b) agree upon the terms of the charter, (c) discuss the research proposed in the U19 project applications and any relevant new information, and set initial priorities for reagents to be derived and for new technologies to be developed. At the first meeting of the Steering Committee following the Planning Meeting, the NIDDK will demonstrate an Internet-based electronic communications mechanism for discussion by the Steering Committee, and will implement the system for the BCB Consortium with any appropriate changes. At the second meeting, the Steering Committee will develop a bioinformatics plan by working in close collaboration with the bioinformatics expertise that is part of the Functional Genomics of the Developing Pancreas Consortium. At this time, the Steering Committee will choose one site that will function as the Bioinformatics Coordinating Center. The Bioinformatics Coordinating Center will be funded in FY 2002. o At their first meeting each year, the Steering Committee will formulate plans for any workshops or symposia to be held. o At the second and subsequent meetings, the Steering Committee will refine the BCB Consortium scientific objectives consistent with progress in the BCB Consortium components and other laboratories. o The Steering Committee will plan one or several workshops a year to which non-BCB Consortium participants will also be invited to enable the BCB Consortium to explore scientific or technologic innovation that occurs during the course of the project. o For the second and subsequent years of operation of the BCB Consortium, the Steering Committee will plan a symposium to inform the research community of the progress made toward developing a cellular therapy for diabetes. The NIDDK Program Coordinator, the NIH BCB Group, and other NIDDK staff will provide the Steering Committee with advice on participants for the workshops and symposia, and manage the logistics for these meetings. o The Steering Committee may establish subcommittees, as it deems appropriate, the NIDDK Program Coordinator will serve on subcommittees as appropriate. NIDDK staff with special expertise may serve on subcommittees at the request of the Steering Committee. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the U19 award) between U19 awardees and the NIDDK may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with the NIDDK Program Coordinator not voting), or by the individual U19 awardee in the event of an individual disagreement, a second member selected by the NIDDK, and, the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. NIH POLICY AND GUIDELINES FOR THE USE OF HUMAN FETAL TISSUE OR HUMAN PLURIPOTENT EMBRYONIC STEM CELLS Applicants must adhere to the current NIH policy and state and federal laws governing the use of either human fetal tissue or human embryos in preparing an application in response to this RFA. Information about the use of Human Fetal Tissue is available at http://grants.nih.gov/grants/guide/notice-files/not93-235.html. Applicants proposing to use NIH funds to conduct research using human pluripotent stem cells derived from human fetal tissue or human embryos must adhere to the Human Pluripotent Stem Cell Research Guidelines available at: (http://stemcells.nih.gov/news/newsArchives/fr25au00-136.asp). To help ensure compliance with these Guidelines, NIH has convened a Human Pluripotent Stem Cell Review Group (HPSCRG) which must review documentation about the derivation of human pluripotent stem cell lines before NIH-funded research can proceed. Information about HPSCRG is available at: (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html). LETTER OF INTENT Prospective applicants are asked to submit, by March 16, 2001, 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 plan the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 653 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) 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 awards. 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: [email protected]. Special Instructions To Applicants 1. General Application Format Instructions In preparing a Beta Cell Biology Program grant, applicants should follow the NIDDK administrative guidelines for preparing a Program Project Grant that are available at (http://www.niddk.nih.gov/fund/divisions/DEA/review_branch/P01guidelines.htm) or from staff listed under Inquiries below. Note, however, that budget caps for the P01 are not applicable to a Beta Cell Biology Program grant. A Beta Cell Biology Program must propose a minimum of 3 projects. Collectively, these projects should demonstrate essential elements of unity and interdependence and result in a greater contribution to program goals, as well as to Consortium goals, than would occur if each project were pursued individually. The relationship and contributions of each research component and core to the overall theme of Beta Cell Biology should be discussed. These programs provide support for research projects as well as common resources and facilities (cores) that are available to individual projects comprising the program. Cores must provide essential functions, services, techniques, determinations or instrumentation that will enhance at least two individual research projects. An administrative core that includes the Data Coordination component is required. In this component, details as to how data that are generated from individual projects will be stored, organized, analyzed, or visualized should be described. Subcontract budgets should be listed on a separate page, and the subcontract indirect costs should be calculated and listed in the usual place as part of the direct costs of the budget. However, only the direct costs associated with each subcontract will count toward the direct costs cap of $1,000,000 on the budget for the first year. The total costs for the applications are not capped. 2. Additional materials The Research Plan should have a section entitled Collaboration of Investigators within the BCB Consortium and other Consortia. In this section, applicants should describe how they believe their unique expertise can contribute to the collective efforts of the BCB Consortium. Applicants must include their specific plans for responding to the Terms and Conditions of Award section. Applicants should state their willingness to collaborate and share data freely with other BCB Consortium components, to participate in planning and attending workshops and symposia, to serve on the Steering Committee and be bound by its decisions, particularly those which relate to setting priorities, and be able and willing to share data and communicate with each other and the NIDDK in an Internet environment. Applicants should include copies of the Material Transfer Agreement used by all the institutions involved in the study. Applicants should also describe how they will comply with the involvement of the NIDDK Program Coordinator, and how they will fulfill the responsibilities of Consortium components to work together cooperatively. Applicants must budget for travel and per diem that will allow the Principal Investigator, and designated Co-PI or senior investigator of an individual Beta Cell Biology Program, to participate in two steering committee meetings each year. Applicants should plan that at least five investigators will attend a workshop or symposium every year in years 2-5. BUDGET INSTRUCTIONS Applicants must follow the NIDDK Administrative Guidelines for the Program Project Grant Application in preparing the budget (http://www.niddk.nih.gov/fund/divisions/DEA/review_branch/P01guidelines.htm). These guidelines include changes in PHS Form 398 and in procedures. Beta Cell Biology Programs cannot request more than $1 million (direct costs) per year or $5 million (direct costs) over five years. An exception to the cap will apply to program applications that include subcontracts. In such cases, the F&A costs related to the subcontracts will be excluded from the requested direct cost levels prior to application of the cap. 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 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. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 653 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS General Considerations 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. Although the technical merit of the proposed protocol is important, it will not be the sole criterion for evaluation of a study. Other factors considered to be important for review include demonstrated expertise in developmental biology, mouse genetics, stem cell biology, functional imaging, or beta cell biology, a multi-disciplinary team of collaborators, substantial interactions among collaborating researchers, demonstration of appropriate facilities and resources, and willingness to share data and reagents freely. Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may 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 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. Review criteria as detailed in the P01 guidelines will be applied and are available at (http://www.niddk.nih.gov/fund/divisions/DEA/review_branch/P01guidelines.htm). In the written comments reviewers will be asked to apply the five standard review criteria (see 1-5 below) to each of the following components of the program in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of the goals of the RFA. Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the cooperative study and their specific protocols, and are expected to address issues identified under SPECIAL REQUIREMENTS of the RFA. The peer review group will assess the scientific merit of the applications and related factors, including: 1. Significance. Do the studies proposed address an important need for the beta cell biology community? What is the immediacy of the research opportunity? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are the standards chosen to characterize and validate a reagent, assay, specific beta cell line or stem/progenitors cells, imaging technology, or animal model sufficient and appropriate? Are these standards generally applicable to all studies in a particular field? Is there an adequate bioinformatics plan to store, organize, analyze, or visualize data that is generated from individual projects? 3. Innovation. Does the project employ novel concepts, approaches, or methods in beta cell biology? Is the project original and innovative? Will the approaches advance the field towards a cellular replacement therapy for diabetes? 4. Investigators. Are the principal investigator and his/her collaborators appropriately trained and well suited to carry out this work? To what extent do these investigators have the necessary complementary skills? Have collaborations been established or consultants identified to provide appropriate depth and breadth of scientific expertise required for the project? Will this team of investigators contribute unique skills to the overall Consortium? 5. Environment. Are the facilities for carrying out the studies appropriate to support the endeavor? 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 and incorporate the best use of collaborative arrangements? Is there evidence of institutional support? 6. Interactions. Are there adequate plans for effective interaction and coordination among program components and the NIDDK? Is there a plan outlined to share data? Do the investigators state their willingness to collaborate extensively and share information fully? Are the Material Transfer Agreements straightforward, or do they involve reach-through agreements? Do the investigators state their willingness to abide by the priorities and policies agreed upon by the Steering Committee? Have the applicants proposed sound strategies for communications among themselves, with the other components of the BCB consortium and with the NIDDK? 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. Schedule Letter of Intent Receipt Date: March 16, 2001 Application Receipt Date: April 17, 2001 Peer Review Date: July, 2001 Council Review: September, 2001 Earliest Anticipated Start Date: September 30, 2001 AWARD CRITERIA The intent of this RFA is to enable the NIDDK to assemble a Consortium composed of highly qualified teams of investigators whose complementary scientific skills and expertise will enable them to gain a comprehensive understanding of the molecular basis of beta cell development and function, and generate new reagents and research tools that could result in the prevention and treatment of diabetes. Applications recommended by the NIDDK Advisory Council will be considered for award based upon (a) scientific and technical merit, (b) the importance of the proposed research in beta cell biology, (c) the degree of originality and innovation in project design, (d) the creativity of the approaches and technologies for the development of reagent, assays, and animal models, (e) the likelihood for substantial contribution by the applicants to a successful collaborative BCB consortium, (f) the evidence for willingness to work cooperatively, (g) the quality and availability of research infrastructure and resources, (h) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood, and (i) the availability of funds. 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: Sheryl M. Sato, Ph.D. Program Coordinator, Cellular Basis of Metabolic Diseases DDEM, NIDDK, NIH 2 Democracy Plaza, Room 6105 6707 Democracy Blvd. MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8811 FAX: 301 480-3503 E-mail: [email protected] Direct inquiries regarding fiscal matters to: Ephraim Johnson Division of Extramural Activities NIDDK 2 Democracy Plaza, Room 610 6707 Democracy Boulevard Bethesda, MD 20892-5458 Telephone: (301) 594-8868 E-mail: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. 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 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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