RFA-DK-01-023: DEVELOPMENT OF THE GUT, LIVER AND EXOCRINE PANCREAS

Department of Health
and Human Services (HHS)

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DEVELOPMENT OF THE GUT, LIVER AND EXOCRINE PANCREAS Release Date: November 14, 2000 RFA NUMBER: DK-01-023 National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov Letter of Intent Receipt Date: March 9, 2001 Application Receipt Date: April 10, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE This initiative is designed to stimulate and solicit studies on gastrointestinal tract, liver and exocrine pancreas development and stem cells. Key research issues to be addressed will be (1) how the developing endoderm gives rise to heterogeneous populations of cells in these developing and adult tissues, and (2) the molecular characterization of stem cells and their immediate descendants. Interdisciplinary projects that focus on basic developmental biology, stem cell biology and relevant clinical conditions associated with the GI tract, liver and pancreas are encouraged. In addition to hypothesis-driven R01 projects, this initiative will encourage development of new research tools through Exploratory/Developmental Grants (R21). 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), Development of the Gut, Liver, and Exocrine Pancreas, 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 by domestic and foreign, for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and exploratory research grant (R21) mechanisms. Except as otherwise noted in this announcement, awards will be administered under policies as stated in the NIH Grants Policy Statement. R01 applications submitted in response to this RFA may not request a total project period of more than five years. In general, the maximum budget request for R01 applications should be limited to $250,000 in direct costs, including facilities and administrative (F&A) costs on consortium arrangements, for each budget year. Exploratory research grant (R21) applications may not exceed two years for the total project period. The maximum budget request for R21 applications may not exceed $100,000 in direct costs for each budget year. The R21 grant mechanism may be used by new investigators or experienced investigators to develop pilot and feasibility studies for new and innovative approaches. R21 applications generally are expected to have little preliminary data and are reviewed based on the development of hypotheses and supporting literature. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH"s National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC Program Director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The anticipated award date is September 30, 2001. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NIDDK intends to commit approximately $3 million in FY 2001 to fund six to eight new research project grants (R01) and six to eight new exploratory research grants (R21) in response to this RFA. Although the financial plans of the NIDDK provide support for this program, 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 GI tract and related organs share common embryological origin from the endoderm. Cross talk between endoderm and mesoderm plays an important role in specifying different components of the gut. The endoderm gives rise to gastrointestinal organs that branch from the main tube (liver, gallbladder, pancreas and cecum). Several genes have been found to be required for bud formation (e.g., Pdx1, Hlx9, Pax4, Pax6, for pancreas and Hex for liver). Subsequent expansion of cellular populations in developing organs is orchestrated by a number of mesenchymal signals, such as Hlx (liver, intestinal epithelium), Pdx1 (pancreas), Cdx1 (intestinal crypts) and NKx2.3 (mid-gut epithelium). Terminal differentiation results from the interplay of both mesenchyme (genes of the Notch/Delta pathway) and epithelium (Shh). Although genes critical for patterning of the early endoderm and organogenesis have been identified, much remains to be understood about these processes. One area that needs considerable attention is the characterization of the stem cell populations in these developing organs. This requires a number of technical advances including identification of surface markers, methods for recovering these cells, clonigenic assays, and implementation of genome anatomy projects that will allow searchable databases of expressed genes to be developed and annotated. Knowledge of the molecular regulation of organogenesis and cell renewal should provide new strategies for treating or preventing a variety of diseases that affect the gastrointestinal tract, exocrine pancreas and liver. For example, the loss, or disruption, of intestinal absorptive function that occurs with inflammatory bowel disease, intestinal resection secondary to vascular disease, trauma, various congenital and neonatal disorders, AIDS enteropathy, and chemo- or radiation-therapy represent major causes of morbidity and impaired quality of life. Currently, the only option for some of these patients is lifelong parenteral nutrition. While further research on small bowel transplantation is encouraged, and may soon provide a therapeutic option for selected patients, research underlying possible strategies to increase the absorptive function of the intestine is needed. Following loss of small bowel surface area, the intestine undergoes an adaptive response that includes increases in the number of proliferative units (crypts), and lengthening of villi. The molecular mechanisms that regulate epithelial cell census and regional differentiation remain poorly defined. One goal of future research in this area will be to use well defined model systems to decipher the complex interplay between environmental factors (e.g., nutrients, the microflora) and intrinsic cellular factors that normally serve to regulate epithelial cell renewal in the intestine. An additional goal will be to develop markers (including surrogate markers) that can be used to monitor various elements of the renewal process. Yet another component will be an assessment of stem cell plasticity as it pertains to the gut. The results of this effort should facilitate development of new means for accurately classifying disease states, new and rational nutritional and pharmacological strategies for preserving the absorptive surface area of the intestine when it is jeopardized, and for restoring it when loss has occurred, and new means for defining the effectiveness of various therapeutic interventions. This need for molecular definition of cellular differentiation and renewal also applies to the liver and pancreas. In recognition of this need, the current RFA includes an extension of a previous initiative (PA-96-079) that encourages research applications for identification and characterization of factors regulating specification and differentiation of cell lineages in the developing and adult liver and biliary tree. The liver has a unique capacity to regenerate after injury. The process begins with proliferation of mature hepatocytes, other cell lineages including biliary epithelial cells (BEC) and sinusoidal cells proliferate somewhat later. When the hepatocytes are prevented from entering the growth cycle by exposure to hepatotoxins or carcinogens, activation of a liver stem cell population is postulated to occur. While the debate on the source and location of hepatic stem cells is ongoing, two recent studies offer a hypothesis to explain the origin of the bipotential oval cell. A number of surface determinants are shared between bone-marrow derived progenitor cells and hepatic oval cells (c-kit,CD34, and Thy-1 in rodents, and c-kit and CD34 in humans). These observations suggest that a population of hematopoietic stem cells originating in the bone marrow may give rise to oval cells in the liver, which in turn, have the potential to further differentiate into hepatocytes and/or ductal cells. Such a concept could have important clinical implications for gene therapy and hepatocyte transplantation, two innovative approaches to the treatment of fulminant hepatic failure and genetic metabolic disorders of the liver. As in the liver, the adult pancreas appears to harbor stem cells that may be induced to proliferate in response to injury. The identification and characterization of progenitor cells that can support expansion of ductal/exocrine cell populations destroyed during acute or chronic pancreatitis, or pancreatic cancer, and factors that control differentiation of the descendants of these progenitors, may provide entirely new approaches for treating these diseases. Research Scope This initiative encourages development of innovative models, approaches and reagents for characterizing the molecular properties of gastrointestinal stem cells and their differentiated descendants, as well as mesenchymal cell populations that may serve to regulate epithelial cell renewal in the developing and adult GI tract, liver and exocrine pancreas. The long-term goal of this effort is to provide a broader conceptual and experimental foundation for understanding the regulation of epithelial renewal in the normal gut and associated organs, characterizing the epithelial-mesenchymal cross-talk that underlies normal development, and for understanding the pathogenesis of disease states affecting the gut, liver, and pancreas. The initiative encourages development of new surrogate markers for identifying and classifying patient populations at risk for development of diseases affecting these organs, for following disease progression, and for characterizing therapeutic responses to existing treatment regimens. Finally, studies supported under this initiative could provide new ways for identifying therapeutic targets and strategies for disease prevention and treatment. Areas of particular focus for R01 grant applications include, but are not limited to: o Analysis of steps in development and maturation of the gastrointestinal tract as well as characterization of gene expression and protein synthesis at the different stages and steps in this orderly development. o Analysis of steps in development and maturation of the liver including hepatocyte and sinusoidal populations. o Analysis of regeneration and growth in the mature gastrointestinal tract, liver and exocrine pancreas. o Identification and functional characterization of the stem cell populations in gut, liver and exocrine pancreas. o Development and/or use of model systems for studies of intestinal, liver and exocrine pancreas regeneration/restitution/adaptation. o Genetic screens for identifying endodermal and mesodermal mutations that influence intestine, liver and exocrine pancreas development. o Growth requirements necessary for expansion of hepatic, pancreatic or gut stem cells in culture and their differentiation. o Regulation of endoderm and mesoderm specification by transcription factors and signaling factors. o Cellular interactions, motility and apoptosis in development and differentiation of intestine, liver and exocrine pancreas. o Role of stem cells in epithelial renewal and how renewal is perturbed in a variety of pathologic states. o Characterization of epithelial-mesenchymal cross-talk that underlies normal development as well as homeostatic mechanisms that operate in adult stem cell populations. In addition to hypothesis-driven studies, this initiative will support exploratory/developmental efforts that seek to develop new resources for the research community. As discussed above, these resources include new methods for rapid recovery of specific cell lineages in both developing and adult GI, liver and pancreas, methods for amplifying and/or retrieving normally rare epithelial lineage progenitors from genetically defined models and the development of clonigenic assays for lineage progenitors, new and broadly applicable methods for amplifying mRNA isolated from single or small numbers of recovered cells so that gene expression profiling can be conducted, and development of systems for inducible expression of gene products in specified cell populations at specified times during development, or in adult animals. Examples of research areas for R21 Exploratory projects on liver, intestine and exocrine pancreas would include, but are not limited to: o Generation of panels of markers for stem cell characteristics that are common across species, for isolation and characterization of stem cells in relevant tissues. o Development of reliable and convenient clonigenic assays for lineage progenitors. o Creation and/or use of new and broadly applicable methods for amplifying mRNA isolated from single or small numbers of recovered epithelial cells so that gene expression profiling can be done. o Development and/or use of innovative and broadly applicable, invasive or non-invasive methods for monitoring gene expression in vivo. o Use and/or identification of cell lines and ex vivo culture conditions that provide useful representations of cell lineages in vivo. o Development and/or use of systems where recombination of target genes can be induced at any time during or after completion of morphogenesis, under selected physiologic or pathologic conditions. o Development of new bioinformatic and computational tools for compiling, annotating, searching and comparing databases of genes expressed in various normal and diseased cell populations in the intestine, liver and exocrine pancreas. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their 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 may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN 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. LETTER OF INTENT Prospective applicants are asked to submit, by March 9, 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 Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) no later than April 10, 2001. Application kits are available at most institutional offices of sponsored research, or may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone 301-710-0267, email: GrantsInfo@nih.gov The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Budget Instructions Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $100,000 per year for R21 exploratory grant applications and $250,000 per year for R01 regular research grants applications. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Indirect costs for subcontracts are included in the total cost budget for the R21 applications submitted in response to this RFA. The subcontract costs should not be in modular format but should be rounded to the nearest $1000. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The 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 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. 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 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 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 The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the applicant employ novel tools, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The reasonableness of the proposed budget and duration to the proposed research will also be reviewed. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. O Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. AWARD CRITERIA The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review, o Availability of funds, o Program priorities. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Michael K. May, Ph.D. DDDN/NIDDK 6707 Democracy Boulevard, Room 663 Bethesda, MD 20892-5458 Telephone: (301) 594-8884 FAX: (301)480-8300 E-mail: MayM@extra.niddk.nih.gov Direct inquiries regarding NIDDK fiscal and administrative matters to: Mrs. Sharon Bourque Division of Extramural Activities NIDDK 6707 Democracy Blvd, Room 612 Bethesda, MD 20892 Telephone: (301) 594-8846 FAX: (301) 480-3504 E-Mail: BourqueS@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93. 93.848. 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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