FETAL ORIGINS OF ADULT DISEASE Release Date: August 10, 2000 RFA: HD-00-021 National Institute of Child Health and Human Development (http://www.nichd.nih.gov/) National Institute on Aging (http://www.nih.gov/nia/) National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov/) National Institute of Environmental Health Sciences (http://www.niehs.nih.gov/) Letter of Intent Receipt Date: September 15, 2000 Application Receipt Date: October 24, 2000 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 The purpose of this solicitation is to determine the mechanisms by which the intrauterine environment programs fetal metabolism to predispose individuals to chronic disease later in life and to determine whether these mechanisms may contribute to disparities in the prevalence of obesity, diabetes, hypertension, atherosclerosis, and neurodegeneration among various races and ethnic groups. The National Institute of Child Health and Human Development (NICHD), the National Institute on Aging (NIA), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute of Environmental Health Sciences (NIEHS) seek to encourage research on the basic mechanisms that may explain the lifelong consequences of intrauterine growth retardation and/or exposure to deficient and/or stressful intrauterine environments. 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), Fetal Origins of Adult Disease, is related to one or more of the priority areas. Potential applicants may obtain "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, 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. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Research Project Grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is August 1, 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 Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The NICHD, NIA, NIDDK, and NIEHS intend to commit approximately $3.8 million in total costs [direct plus Facilities and Administrative (F&A) costs] in FY 2001 to fund seven to 10 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to five years. Because the nature and scope of the research proposed may vary, it is anticipated that the size of awards also will vary. Although the financial plans of the NICHD, NIA, NIDDK, and NIEHS provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds, the receipt of a sufficient number of meritorious applications, and relevance to programmatic interests of the participating institutes. RESEARCH OBJECTIVES Background The problem of health disparities in the United States, particularly the high prevalence of obesity, hypertension, stroke, Type 2 diabetes, and coronary artery disease in minority populations, may result in part from interactions of the fetus with its intrauterine environment. Epidemiologic studies have demonstrated that low birth weight and, more specifically, intrauterine growth retardation are associated with insulin resistance, Type 2 diabetes mellitus, hypertension, coronary artery disease, and lowered cognitive performance later in life. A prospective case-control study has shown that levels of amniotic fluid insulin predict obesity and insulin resistance later in life. Based on these observational studies, it has been suggested that metabolic programming occurs during fetal life in response to intrauterine growth constraints and/or exposure in utero to deficiencies or surfeits of nutrient substrates, oxygen, hormones, growth factors, and cytokines. While epidemiological studies have identified the phenomenon of metabolic programming, little is known about the mechanisms by which fetal insults lead to disease later in life. At the most general level, metabolic programming represents a fetal response to accommodate an inimical intrauterine environment in order to optimize chances for fetal survival. In its drive for survival, the fetus appears to favor the metabolic demands of the growing brain over the metabolic demands of the kidneys, liver, muscle, pancreas, and other organs. The molecular mechanisms that govern this phenomenon are unknown and need to be elucidated, especially because the intrauterine survival advantage gained by this maneuver may entail a cost of metabolic impairment and chronic disease later in life. For example, deprivation of intrauterine nutrient supply to the kidney may result in fewer nephrons than normal with a reduced filtration capacity, paving the way for hypertension later in life. Similarly, impaired substrate supply to the pancreas during fetal development may result in a smaller than normal beta cell mass leading to glucose intolerance later in life. Whether, in fact, these intrauterine accommodations lead to chronic disease later in life remains to be established. Other mechanisms beside blood flow redistribution may account for the observed associations between low birth weight and chronic disease later in life. In fact, the more general question of fetal metabolic response to the intrauterine environment, whether stressed or nutrient restricted or not, may have implications for health and disease later in life. This is a key issue that needs to be studied in depth. In order to do so, more precise predictors of chronic disease are needed in addition to the anthropometric markers currently in use such as birth weight, birth length, and ponderal index. Biochemical or genetic markers may more accurately reflect fetal metabolic programming and predict chronic disease and health disparities later in life. Such biochemical and genetic markers need to be determined, and research directed towards this aim is of the highest priority. Research Scope To address these research needs, this RFA seeks research projects focused on one or more of the following goals: (a) To identify biochemical and genetic markers during fetal and early postnatal life for prediction of risk for chronic disease and disabilities later in life. (b) To elucidate the effect of psychosocial stress during pregnancy on fetal growth, metabolism, neuroendocrine development, and behavior later in life. (c) To ascertain the mechanisms by which the fetus senses an intrauterine environment that is deleterious for brain development and responds by shunting blood away from other organs to the brain. (d) To develop interventions designed to mitigate the metabolic derangements associated with intrauterine growth retardation and its consequences for adult disease later in life. Research Topics Relevant research topics include, but are not limited to, the following: o Potential mechanisms by which the normal fetal growth trajectory goes awry, including impaired placental function and the pathogenesis of placental malfunction. o Placentation and fetal growth, including placental-fetal interaction, with emphasis on the molecular mechanisms by which the fetus provokes compensatory placental functions. o Elucidation of the molecular and genetic mechanisms by which the fetus adapts to its intrauterine environment, including especially the phenomenon of metabolic programming. o Interactions among nutrients, trophic hormones, cytokines, and genes and their effect on fetal growth and long-term development. o Late-life neural, cognitive, and behavioral sequelae of fetal perturbations. o Effect of perturbations of the intrauterine environment on fetal cardiovascular development and blood pressure regulation later in life. o Effects of maternal psychosocial stress on the development of the hypothalamic-pituitary-adrenal axis in the offspring, including long-term consequences and intergenerational effects on behavior and organ and system function. o Effects of intrauterine environments on beta cell development, beta cell mass, glucose sensing, insulin signaling, and insulin action. o Metabolic programming and insulin resistance in multiple generations in both humans and animal models. o Identification of subsets of growth-retarded fetuses at high risk for metabolic derangements later in life. o Elucidation of the mechanisms that account for the metabolic derangements that ensue when growth-retarded newborns are exposed to a surfeit of food during infancy and childhood, and how these derangements lead to chronic metabolic disease later in life. o Development of interventions designed to mitigate the metabolic derangements of intrauterine growth retardation and its consequences later in life. Studies are needed to determine if limiting caloric intake during infancy and childhood can ameliorate the impact of intrauterine growth retardation. o Elucidation of the interrelationship between the socioeconomic and health environment early in life and its consequences later in life on health, disability, and survival. o Interactions of genes and the intrauterine environment as determinants of disease later in life. Research Resources Applicants are encouraged to exploit existing longitudinal multi-generational cohorts with stored maternal and fetal serum to assess the contributions of the intrauterine environment to adult conditions later in life. Applicants also are encouraged to utilize existing animal models or to develop new animal models to address the issues of maternal stress during pregnancy and consequences of metabolic programming during fetal life. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and available on the Internet at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available on the Internet at: 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. 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. LETTER OF INTENT Prospective applicants are asked to submit 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 this RFA. 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 NICHD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Gilman D. Grave, at the address listed under INQUIRIES, below, by September 15, 2000. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, and 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, E-mail: grantsinfo@nih.gov. Application Instructions 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 NIH 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. For responses to this RFA, Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) 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: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the Total Direct Costs requested for each year. This is not a Form Page. 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 F & A) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the Form Page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years; - List selected peer-reviewed publications, with full citations. o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and telephone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the RFA number HD-00-021. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is in the pdf format. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, 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 should be sent to: L. R. Stanford, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Blvd., Room 5E01, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-9254 Applications must be received by October 24, 2000. 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 Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness to the RFA by NICHD, NIA, NIDDK, and NIEHS staff. 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 NICHD 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 will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council of NICHD, NIA, NIDDK, and/or NIEHS. 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. (1) 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? (2) 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? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (5) 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 also will be reviewed with respect to the following: o The 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 in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Schedule Letter of Intent Receipt Date: September 15, 2000 Application Receipt Date: October 24, 2000 Peer Review Date: February/March 2001 Council Review: June 2001 Earliest Anticipated Start Date: August 1, 2001 AWARD CRITERIA Criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Potential applicants are strongly encouraged to contact program staff with any questions regarding the responsiveness of their proposed project to the goals of this RFA. Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. A complete listing of contacts for both programmatic and fiscal/administrative inquiries may be found at: http://www.nichd.nih.gov/RFA/HD-00-021/HD-00-021.htm AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.113, 93.865, 93.866, and 93.849. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 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 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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