NIDDK PROGENITOR CELL GENOME ANATOMY PROJECTS Release Date: October 9, 2001 RFA: RFA-DK-02-027 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) Letter of Intent Receipt Date: February 15, 2002 Application Receipt Date: March 15, 2002 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites Cooperative Agreement Applications for Progenitor Cell Genome Anatomy Projects (GAPS) that will participate in the discovery of the processes necessary for development of tissue specific cells and organs from stem cells and the processes by which progenitor cells maintain and regenerate tissues and organs in health and disease. The specific goals of the projects will be to develop the necessary biological procedures and reagents for characterization of tissue specific progenitor cells and to characterize gene expression patterns in these cells using advanced technologies and bioinformatic techniques. The focus of the projects will be on progenitor cells of the gastrointestinal tract, liver, pancreas, kidney and genitourinary tract in both human and murine systems. Because of the nature of the research questions, it is expected that potential applicants will include both investigators with expertise in the biology of progenitor cells and investigators having substantial expertise in bioinformatics. The components of the GAPS will work together as a consortium It is expected that the consortium will serve as a resource to provide reagents and databases that will be made available to the research community. The Human Genome Project and similar work in other species have made it possible to address in new ways the important biological problems of how different tissues and organs develop from small founder populations of stem cells, how organs continue to be maintained and sometimes regenerate during adult life, and the effects of age and disease on this capacity. While less is known about development of endodermal organs, such as the liver and pancreas, than about ectodermal and mesodermal tissues, such as skin and blood, recent advances have demonstrated two important principles. First, work in model experimental organisms suggests that some critical molecules that regulate organ development are evolutionarily conserved. Second, there is emerging evidence that progenitor cells of different tissues may share some common basic molecular mechanisms that allow them to self- renew in the presence of appropriate environmental cues. The elucidation of these mechanisms offers the promise of providing a complete understanding of the factors that maintain normal tissues in health and the promise for novel approaches to the study of pathogenesis and treatment of human diseases. Therefore, the aim of these projects will be to accelerate progress toward identification and characterization of progenitor cells and factors that regulate development and differentiation of the gastrointestinal epithelium, liver, exocrine pancreas and kidney and urologic tissues, including prostate and bladder. As a related NIDDK initiative already is directed at the endocrine pancreas and hematopoietic stem cells (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-02-018.html), these cell types are specifically excluded from this initiative. This grant award mechanism will support characterization of appropriate stem cell lines that are broadly relevant to study of the target organ at multiple stages of target organ development and differentiation, determination of gene expression patterns in those cell lines, and development of appropriate functional genomics tools to characterize the genes expressed. In addition, this resource will provide bioinformatics links to existing NIH-supported genomics databases and make relevant biomarkers and genomics tools available to be used by researchers investigating both normal and diseased tissue. 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. This Request for Applications (RFA), NIDDK PROGENITOR CELL GENOME ANATOMY PROJECTS, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted from either domestic or foreign institutions, for-profit and non-profit 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. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. Among the disciplines and expertise that may be appropriate for this program are gastroenterology, nephrology, urology, hematology, internal medicine, pediatrics, genetics, bioinformatics, pathology and related scientific disciplines. MECHANISM OF SUPPORT This RFA will use the NIH cooperative research (U01) award mechanism of support, 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 stimulate the recipients’ activity by involvement in the activity and otherwise working jointly with the award recipients in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreements are discussed below under “Terms and Conditions of Award.” 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 $1,500,000 in direct costs for the initial budget period and $4.5 million in direct costs for the entire project period. Projects of varying budget and size are encouraged. This is a one time solicitation. The anticipated award date is September 30, 2002. FUNDS AVAILABLE For FY 2002, $4M in total costs will be committed to fund applications submitted in response to this RFA. Since applications for projects of various sizes are encouraged, it is anticipated that –two to four awards will be made. 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 19, 2000, the NIDDK convened a Working Group of its National Advisory Council to develop strategic plans for several cross- cutting areas of research, including Stem Cells and Developmental Biology. The primary recommendation of this group was that NIDDK should catalyze a nation-wide effort to characterize the molecular and cellular features of stem cells during and following development of the pancreas, liver, stomach and intestine, kidney and GU tract, bone, and hematopoietic tissues. The goal is to provide entirely new strategies for repairing or replacing damaged organs in individuals of all ages, and new insights about pathologic processes underlying disordered development, disordered maintenance, and neoplastic transformation of these organs. Genome Anatomy Projects (GAPs) have been established by the National Cancer Institute and NIDDK to accelerate the pace of discovery of genes expressed in specific tissues, such as tumors or the endocrine pancreas, and to exploit the sequence data emanating from the Human Genome Project. The GAPs foster the development of national networks of laboratories that characterize tissue-specific gene expression and identify novel transcripts. In addition, GAP researchers elucidate patterns of gene expression that lend insight into developmental programs and disease progression, and that may eventually be useful in diagnosis and treatment of disease. The bioinformatics systems associated with each GAP ensure that all of the data produced are available to researchers worldwide soon after it is generated in the laboratories. Given the importance of developing new in vivo models for studying and assaying stem cell function, the need for improved isolation and recovery of stem cells, and the need for methods to maintain ex vivo cell populations that retain their pluripotency, it is essential to characterize genomic features of stem cells and their committed daughters. The status of research on stem cells or progenitor cells in different organ and tissues varies widely. For example, hematopoiesis is among the best-understood biological systems in mammals. Purification of adult hematopoietic stem cells (HSCs) through the use of monoclonal antibodies such as CD34 has been accomplished, however imperfectly, and lineage-specific progenitors have also been purified recently. HSCs are also used for liver repopulation, but the factors that permit the conversion of HSCs to hepatocytes remain to be discovered. In addition, there is some evidence for liver stem cells. In the gut, epithelial renewal in the stomach, small intestine, and colon is sustained by populations of multipotent stem cells that reside in distinct anatomic units. However, the properties of these stem cells remain to be more fully defined. Finally, the stem cell biology of the prostate, bladder and kidney is largely unknown, with the features and location of these stem cells mostly undefined. For these tissues, there is a need for the establishment of reproducible conditions and protocols for the identification, retrieval, and maintenance of stem or progenitor cells. The current RFA is designed to stimulate GAPs that will catalogue the gene expression in recovered stem cell or progenitor cell populations in developing and adult normal tissues and provide that information and material, along with relevant functional genomics tools, to the entire research community. Since the databases for the GAPs will perform similar functions, it should not be necessary for multiple sites to invent similar database methods in parallel. Therefore, researchers from the GAPs will develop robust and generic modules to perform particular tasks, so that all databases share a common architecture, regardless of the underlying database platform. Although developing a module in a robust and generic manner so that it is usable by other projects takes more effort than developing it to work within just a single GAP, the modular structure will make it easier for the general research community to search among the data collected by the various GAPs, and will facilitate sharing among the GAPs, comparisons, and data mining. Objectives and Scope This RFA is intended to support the cost-effective determination of the gene expression profiles in the targeted stem or progenitor cell populations of human or murine origin and to develop functional genomics tools to characterize the genes expressed. The relevant tissues for this initiative are: developing and adult exocrine pancreas (the endocrine pancreas is excluded from this initiative), liver, stomach/intestine, kidney/bladder, bone and fat. Thus, all applications must include separate sections describing each of the listed aspects of the project. Since stem cell research is at different stages of development for each of the targeted tissues or organ systems, it is anticipated that each project will allocate resources differently to the various parts of the GAP. Nevertheless, each application must include: o Characterization and Definition of Cell Populations – Define and/or develop specific biomarkers, such as high-specificity antibodies or reporter gene constructs, for detection, classification, and isolation of stem cells and progenitors at multiple stages of development and differentiation, as well as those specific to particular lineages. This will include, where appropriate, development of reliable and convenient clonogenic assays for stem cell populations in developing and adult tissues so that these cells can be purified and characterized. In addition, this part of the GAP may include development of methods to maintain ex vivo cell populations that retain their pluripotency. o mRNA Expression Profile – Profile mRNA expression in the relevant cell populations and identify novel genes and transcript splice forms specifically expressed in the targeted cell population using in silico methods, production and sequencing of cDNA libraries, as well as arrays and other methods. 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 over- represented or known genes. In addition, the application should describe the development of custom clone sets for use in microarrays or other high-throughput gene expression assays, and the use of those arrays to characterize changes in gene expression patterns in the target cell population during development, differentiation, or disease progression. Finally, this phase of the project may also include efforts to develop and apply single-cell gene expression methodologies. o Histology and Functional Genomics - Develop rapid, sensitive methods for in vivo confirmation of patterns of gene expression. This phase of the project may also include the development of one or more gene- specific tools, such as reporter gene (e.g. with Green Fluorescent Protein, beta-galactosidase) and antisense constructs, conditional or nonconditional knockout mutations, and morpholinos or other inhibitors of expression, for characterizing the cell lineage under study and for analyzing the role of particular genes. o Database – Although each GAP will develop its own database to store, organize, analyze, or visualize data, this database will be based on common modules developed by all the funded GAPs. A module will be included that allows for Internet-based comparisons of progenitor cell gene expression data to similar data obtained from normal and diseased tissues from model organisms and humans. The overall goal is that GAP databases should be easy to search and clearly illustrated. Applicants should discuss how they would participate and contribute to this modular approach and summarize their experience in this area. A schedule for rapid disposition of sequences and expression data into public databases such as GenBank and the Gene Expression Omnibus (GEO) should also be proposed. o Research Tool Distribution – Develop and distribute to the research community well-characterized progenitor cells, cDNA clones, and high- specificity antibodies. In addition, the GAP should develop and distribute clone sets or long oligonucleotides for printing custom microarrays that can be used to identify and characterize the target stem cell population during different stages of development and differentiation. Similarly, the project should develop and distribute any functional genomics tools developed, including Green Fluorescent Protein (GFP) or antisense constructs, knockout cell lines or vectors for gene replacement, and other similar reagents that can be used to isolate and study the target cells at various stages and/or study the role of specific genes. The selection of sequences for custom arrays and reporter constructs should be well-justified and based on their utility for research on the relevant stem cell. The application should describe plans to develop and maintain supporting informatics and easily accessible Web sites that describe available tools and validated methods. Plans for distributing reagents in a timely and economical fashion should be included. o Outreach - A major objective of this RFA is to disseminate the data and research reagents generated through each project to the research community as rapidly as possible. Therefore, the application should describe methods for ensuring that the larger research community has access to data and available tools generated by the GAP. In addition, applicants are encouraged to describe opportunities for long- and short-term training of researchers at all levels to take advantage of these data and reagents. SPECIAL REQUIREMENTS Applicants must indicate their willingness to be part of a Steering Committee consisting of representatives of each GAP funded by NIDDK through this RFA and through RFA-DK-02-018 and NIH staff. The semi- annual meetings will be held to encourage exchange of information among investigators who participate in this program. 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 also discuss quality assurance, coordination, sharing, means of informing the research community of services offered by the GAPs, and training. One special focus of the meetings will be on bioinformatics and the construction of common modules that will be used by all GAP databases. Applicants must include travel funds that will allow the Principal Investigator and the key research scientist leading the bioinformatics effort to participate each year in two one-day meetings in Bethesda, Maryland. During the course of the funding period, technologies will improve, and the rate of progress and focus of work supported by the cooperative agreement may change. It is expected that the Principal Investigator(s), in consultation with NIDDK program staff, the Steering Committee, and the External Advisory Board (see below) will make any necessary adjustments to accommodate the changing research environment, to remain focused on appropriate goals, to maintain excellent coordination with the other projects funded by NIDDK, and to incorporate new technological advances. A. Interactions The GAPs, through the Steering Committee, and other subcommittees will: o Share bioinformatics expertise and software tools to develop robust database software as modules to perform particular tasks. Such modules will be able to read and write data in certain common formats, but will be independent of the underlying database platform. These modules will provide uniformity of data presentation between the GAPs, and facilitate distribution of resources between component Units and with the broader research community. The modules developed may include modules for storing and presenting microarray data, cell-type-specific expression profile, annotation data for expressed genes, and in vivo expression data, as well as various queries or views that are generally useful. o Define the best practices and develop controlled vocabularies to describe genes, tools and reagents, o Identify technological impediments to characterizing gene expression, or generating appropriate tools, and select strategies to surmount them, o Share technological and methodological information both between component GAPs and with the broader research community, o Share molecular tools and constructs between GAPs to avoid unnecessary duplication of effort, At each step, input will be sought from experts both within the GAPs, those funded through other NIDDK-sponsored initiatives, such as the Functional Genomics of the Developing Endocrine Pancreas (RFA-DK-99- 007), NIDDK Biotechnology Centers (RFA-DK-00-002), and Development of the Gut, Liver and Exocrine Pancreas (RFA-DK-01-023), and from the broader research community. B. Genome Anatomy Project Individual Units Each Unit will be a self-assembled group of investigators from one or more institutions who provide a unique mix of complementary research experiences. An applicant team will incorporate an appropriate mix of expertise needed to achieve the Unit’s goals and to contribute substantially to achieving the overall GAP Consortium goals. Units will be expected to focus on either one or a small number of tissues. Each team must contain expertise in stem cell biology, genomic analysis, bioinformatics, and pathology The approaches used to generate the appropriate progenitor cell line or lines, and characterize the gene expression profile will reflect the blend of experience and creativity of the component investigators. It is anticipated that some of these applications will be quite speculative, and applications may have limited preliminary data on the properties of progenitor cells in some specific organs. However, applications should include sufficient information to indicate that the applicant team has sufficient expertise with proposed techniques and that the proposed projects are feasible. C. Data Sharing Restricted availability of unique research resources, upon which further studies are dependent, can impede the advancement of research and delivery of medical care. Sharing biomaterials, data, and software in a timely manner has been an essential element in the rapid progress that has been made in the genetic analyses of mammalian genomes. NIH policy requires that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication [NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps, Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html)]. Biomaterials (constructs, cell lines, etc.) and other research resources that can be patented (e.g., software tools, expression data) produced in projects funded by this RFA are expected to be made available and distributed to the broader scientific community. The NIH is interested in ensuring that the research resources developed through this RFA become readily available to the research community for further research, development, and application, in the expectation that this will lead to products and knowledge of benefit to the public. At the same time, NIH recognizes the rights of grantees to elect and retain title to subject inventions developed under federal funding under the provision of the Bayh-Dole Act. This RFA has two special requirements regarding research resources produced in proposed projects: (1) Applicants are required to include in their application a specific plan by which they will share research resources with the wider scientific community, as well as copies of all Material Transfer Agreements used by all institutions involved in the application. (2) Applicants are required to include a plan addressing if, or how, they will exercise their intellectual property rights while making available to the broader scientific community patentable research resources. These plans should be consistent with the policies of their institutional offices of technology transfer. The scientific review group will evaluate the adequacy of the proposed plans for sharing and data access. Comments on the plan and any concerns will be presented in an administrative note in the Summary Statement. The adequacy of the plan will be considered by NIH program staff and will be important in determining whether the grant shall be awarded. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. Evaluation of non-competing continuation applications will include assessment of the effectiveness of research resource release. Applicants are reminded that the grantee institution is required to disclose each subject invention to NIH within two months after the inventor discloses it in writing to grantee institutional personnel responsible for patent matters. The awarding Institute reserves the right to monitor awardee activity in this area to ascertain if patents or patent applications on mice identified through phenotypic screens, phenotypic screens, and phenotypic and genotypic data for all mouse strains or other patentable subject matter are adversely affecting the goals of this RFA. E. Steering and Other Committees The Principal Investigator must be willing to be part of a Steering Committee that will meet twice each year together with NIH program staff to encourage exchange of information among investigators who participate in this program. The Steering Committee may form other committees (for example, bioinformatics, technology) that will meet once or twice a year either in person or by telephone conference calls. A major goal of these meetings is to facilitate progress by providing a forum for sharing skills, ideas, technology, data, and biological reagents. At the meetings, participants will also discuss quality assurance, bioinformatics, coordination, and training. If voting is necessary for an action item, NIH Project Scientists will share one vote. TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) and to the institutional official at the time of 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, PHS, and NIH Grant Administration policy statements. 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(s) will serve as voting member[s] of the Steering Committee, will attend the Planning Meeting and a Steering Committee meeting in the first year, and two Steering Committee meetings a year in subsequent years. o The PI will be responsible for accepting and implementing the goals, priorities, procedures, protocols, and policies agreed upon by the Steering Committee and subcommittees. o The PI will be responsible for close coordination and cooperation with the other GAPs and with NIH staff. o The PI will establish an Internal Advisory Committee to provide scientific and administrative oversight. The Internal Advisory Committee will be composed of the lead center personnel, and other technical or research personnel. These individuals are not limited to GAP faculty. The committee is expected to meet at least monthly. Minutes of these meetings will be made available to NIH staff upon request. The Internal Advisory Committee is charged with both prioritizing projects and periodically reviewing GAP activities to ensure that the objectives outlined in the application are being met. 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. However, all awardees must adhere to PHS policy for the distribution of unique research resources produced with PHS funding as described under Special Requirements. The NIDDK Project Scientists, on behalf of the NIDDK, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee. o NIH reserves the right to require the transfer of appropriate cell lines, reagents, tools 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 these materials and data about them and/or to continue the research. Third parties supported under these awards must be informed of this right. o Within the first three months of the award period, the PI will be responsible for establishing written milestones for the GAP, in consultation with NIDDK Project Staff. o Support or other involvement of industry or any other third party in any study performed by the GAPs-- e.g., participation by the third party, involvement of project resources or citing the name of the project or the NIDDK support, or special access to project results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification to, and concurrence by, NIDDK. o Upon completion of the project, the GAPs are expected to put all study design materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NIDDK, for the conduct of research at no charge other than the costs of reproduction and distribution. 2. NIH Staff Responsibilities NIDDK Project Scientists will have substantial scientific-programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. The dominant role and prime responsibility for the project as a whole resides with the awardees, although specific tasks and activities in carrying out the studies will be shared by awardees and the NIDDK. o NIDDK will designate a Project Officer and a Grants Management Specialist to provide administrative oversight of the cooperative agreement. o NIDDK will form an External Advisory Committee, comprised of NIDDK Project Staff and other NIH extramural staff with relevant scientific expertise or who manage research grant programs that relate scientifically to the goals of the GAPs, and outside advisors picked by the NIDDK. The External Advisory Committee will meet regularly to review the progress of the GAPs and to advise NIDDK Project Staff of scientific developments and opportunities that may enhance the achievement of the GAP goals. o NIDDK Project Scientists will be members of the Steering Committee and, as determined by that committee, its subcommittees. o NIDDK Project Scientists will coordinate and facilitate the GAPs, attend and participate as voting members in all meetings of the Steering Committee, and provide liaison between the Steering Committee and the External Advisory Committee. o NIDDK Project Scientists will help the Steering Committee develop and draft operating policies and policies addressing recurring situations that require coordinated action. o NIDDK Project Scientists will review the scientific progress of the individual GAPs, review GAPs for compliance with operating policies developed by the Steering Committee, and may recommend to the NIDDK to withhold support, suspend, or terminate an award for lack of scientific progress or failure to adhere to policies established by the Steering Committee. 3. Collaborative Responsibilities Steering Committee - The NIH Project Scientists and PIs of the GAPs funded under this RFA and RFA-DK-02-018 will be responsible for forming a Steering Committee as defined below. An arbitration system, as detailed below, will be available to resolve disagreements among members of the Steering Committee. The Steering Committee will be the main governing board of the GAPs. It will develop collaborative protocols, identify technological impediments to success and strategies to overcome them, develop shared software tools for disseminating information about the GAPs, and identify opportunities for sharing techniques and tools developed within each individual GAP. o The Steering Committee will be composed of the PI from each GAP funded through this RFA and RFA-DK-02-018, and NIDDK Project Scientists. The PI from each GAP will have one vote. The NIDDK Project Scientists will share one vote. The Steering Committee will select a chairperson who will be someone other than an NIDDK staff member. o The Steering Committee may, as it deems necessary, invite additional, non-voting scientific advisors to meetings at which research priorities and opportunities are discussed. The NIDDK reserves the right to augment the scientific or consumer expertise of the Steering Committee when necessary. o There will be two Steering Committee meetings annually, both in the Washington, DC, area at times agreed upon by the Steering Committee and the NIDDK. o The first meeting of the PIs from GAPs funded under this RFA and RFA DK-02-018 will be a Planning Meeting in the Washington, DC, area soon after grants are awarded. At the Planning Meeting, the Steering Committee will be formed and select a chairperson from among the members who represent the awardees. At the Planning Meeting, the Steering Committee may: (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 NIH Project Administrators 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 approaches that were proposed in the project applications and any relevant new information, and set initial priorities for the projects to be pursued and for new technologies to be developed, (d) develop a bioinformatics subcommittee whose membership will include the key research scientist from each GAP responsible for bioinformatics, NIDDK Project Staff, and outside advisors as needed. o The bioinformatics subcommittee will work together to develop a uniform database architecture, deciding on which modules are needed and developing those modules for use by all GAPs. 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 GAPs’ scientific objectives and implementation as necessary, consistent with progress in the individual GAPs and other laboratories. o The Steering Committee will plan workshops to which non-GAP participants will also be invited to (a) enable the GAPs to explore scientific or technologic innovation that occurs during the course of the project, (b) inform the research community of the progress made toward development of gene expression profiles and progenitor cell lines, and (c) inform the research community of any technological advances related to implementation of a GAP. The NIDDK Project Scientists, the External Advisory Committee, and other NIH staff will provide the Steering Committee with advice on participants for the workshops and symposia. o The Steering Committee may establish other subcommittees, in addition to the bioinformatics subcommittee, as it deems appropriate, NIH Project Scientists and other NIH staff who are Steering Committee members will serve on subcommittees as they deem appropriate. 4. Arbitration Any disagreement that may arise on scientific and programmatic matters within the scope of the cooperative agreement and between award recipients and NIDDK may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the GAP Principal Investigator, a second member selected by 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 appealable in accordance with 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. 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 also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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 Applicants must adhere to the current NIH policy and state and federal laws governing the use of human fetal tissue 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent by February 15, 2002. The letter should include 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 IC 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 National Institute of Diabetes and Digestive Kidney Diseases 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 FAX: (301) 480-3505 E-mail: fc15y@nih.gov APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. The NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/435-0714, Email: GrantsInfo@nih.gov. SPECIAL INSTRUCTIONS General Application Format Instructions The form PHS 398 should be modified as follows. Biosketches and "Other Support" pages should be included for all personnel. The number of pages allowed for the "Research Plan" is increased from 25 to 40 pages. Budget pages, budget justifications, material transfer agreements, and letters from collaborators and consultants and their biosketches are not included in this limit. As described in detail above in RESEARCH OBJECTIVES (Objectives and Scope), applicants should divide the "Research Plan" into six sections: 1)Characterization and Definition of Cell Populations, 2) mRNA Expression Profile, 3) Histology and Functional Genomics, 4) Database, 5) Research Tool Distribution, and 6) Outreach. In all sections, the roles and expertise of all key personnel, collaborators, and consultants who are associated with this part of the application should be well documented. Applicants must provide methods to maintain GAP records, establish, standardize, document, and distribute protocols, and provide for quality control and budgetary oversight. Applicants must also provide methods to establish priorities among the proposed projects and to oversee the daily operation of Units. The application should include the description of the internal advisory board consisting of the Principal and co-Investigators and other important personnel that will oversee the daily operation of the Unit. Applicants should describe how the GAP will fit into, augment, and be supported by the parent institution and plan for designating an alternate or replacement Principal Investigator should it become necessary. In this part of the "Research Plan," applicants must include specific plans for responding to the "SPECIAL REQUIREMENTS" section. Applicants should state their willingness to collaborate and share data freely with the other GAPs and the wider research community. Applicants must include a data sharing plan and copies of all Material Transfer Agreements used by all institutions involved in the application. Applicants are encouraged to use the NIH Simple Letter of Agreement to transfer materials, available at http://www.ott.nih.gov/policy/rt_guide_final.html#guide. Applicants should discuss their willingness to serve on the Steering Committee and other Consortium committees and should state their willingness to follow the common protocols that will be developed by the Steering Committee. Applicants must state their willingness to plan and attend workshops and symposia. Applicants should also describe how they will comply with the involvement of NIH Project Scientists and fulfill the responsibilities of Consortium components to work together cooperatively. Applicants should describe their experience with, and capability for developing modular database tools that can be shared. In addition, applicants should describe their experience with Internet-based communication and suggest ideas for facilitating electronic communication and other interactions among the GAPs, NIH, and the general research community. Budget Instructions Applicants who have additional funds to support (‘leverage’) the application should indicate the source of funds (institutional, R01, P01, P30, etc.) that permit them to accomplish the project goals. Subcontract budgets should be 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 direct costs associated with each subcontract will count toward the direct costs cap of $1,500,000 on the budget for the first year. Applicants must budget for travel and per diem expenses for participation in the Steering Committee, subcommittees, workshops, and symposia. Applicants should budget for seven trips to the Bethesda, MD, area each year. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number(DK-02-027) on the label. 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 RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Dr. Francisco O. Calvo Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8897 E-mail: fc15y@nih.gov Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. 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 already 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 progenitor cell biology, a multi-disciplinary team of collaborators, substantial interactions among collaborating researchers, demonstration of appropriate facilities and resources, willingness to share data and reagents freely. Supplemental information of up to three single-sided pages, to include figures and photographs will be allowed if received by June 17, 2002 (this is an approximate date based on a review schedule of July or August 2002). Send materials to Chief, Review Branch, at the address above. Review Method Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete 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 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 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 they are expected to address issues identified under “SPECIAL REQUIREMENTS,” ”TERMS AND CONDITIONS OF AWARD” and ”SPECIAL INSTRUCTIONS” sections of the RFA. The peer review group will assess the scientific merit of the applications and related factors using the following criteria: Significance. The application should address the problem outlined in the RFA. The application should demonstrate how the study would advance scientific and/or medical knowledge. Do the cell types chosen for expression profiling address important needs of the larger research community? What is the immediacy of the research opportunity? Innovation. Does the project employ novel concepts, approaches or method? Is the project original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Will the approaches advance the field of hematopoietic cell development? 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? 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 the appropriate depth and breadth of scientific expertise required for the project? Will this team of investigators contribute unique skills to the overall Consortium? There should be evidence of prior experience in working collaboratively to carry out a standard protocol as well as evidence of willingness to work cooperatively on the Steering Committee to develop and follow a unified protocol. Environment. Are the facilities for gene expression profiling, functional genomics, and bioinformatics 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? Additional Considerations Interactions. Are there adequate plans for effective interaction and coordination among Consortium components and the NIH? Are the proposed plans to share data and tools adequate? Do the investigators state their willingness to collaborate extensively and share information fully? Are the Material Transfer Agreements straightforward? 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 communication among themselves, with the other GAPs and with the NIH? Have the applicants proposed sound strategies and approaches for working collaboratively to develop common database modules? Reasonableness of the proposed budget and duration appropriate in relation to the proposed research: Does it indicate that the applicants understand the requirements of managing this sort of high- throughput genomics enterprise? 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, protection and retention of human subjects also will be evaluated, as will the safety of the research environment. Schedule Letter of Intent Receipt Date: February 15, 2002 Application Receipt Date: March 15, 2002 Peer Review Date: July, 2002 Council Review: September 2002 Earliest Anticipated Start Date: September 30, 2002 AWARD CRITERIA Applications recommended by the NDDK Advisory Council will be considered for award based upon (a) scientific and technical merit as determined by peer review, (b) the importance of the proposed cell types for research, (c) the degree of originality and innovation, (d) the creativity of the approaches and technologies, (e) the likelihood for substantial contribution by the applicants to a successful collaborative effort, (f) the evidence for willingness to work cooperatively, (g) program balance, and (h) 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: Rebekah S. Rasooly, Ph.D. Genomics Program Director Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health 6707 Democracy Blvd, Room 643 Bethesda, MD 20892-5458 Telephone: (301) 594-6007 FAX: (301) 480-3510 E-mail: rr185i@nih.gov Direct inquiries regarding fiscal matters to: Donna Huggins Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health 6707 Democracy Boulevard, Rm. 711 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8848 FAX: (301) 480-3504 E-mail: dh48v@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.849. 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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