EXPLORATORY GRANTS FOR GENOMIC IMPRINTING AND ENVIRONMENTAL DISEASE SUSCEPTIBILITY Release Date: December 22, 1999 PA NUMBER: PA-00-034 National Institute of Environmental Health Sciences THIS PROGRAM ANNOUNCEMENT (PA) USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THE PA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute of Environmental Health Sciences (NIEHS) invites research grant applications from interested investigators to conduct timely, innovative, and mechanistic research on the importance of genomic imprinting in determining susceptibility to environmentally induced diseases through a program of exploratory investigator-initiated R21 grants. The exploratory/developmental (R21) grant mechanism is used for pilot projects or feasibility studies to support creative, novel, high risk/high payoff research that may produce innovative advances in science. This PA is to encourage applications from individuals who are interested in testing novel or conceptually creative ideas to understand the potential role environmental agents play in causing epigenetic changes in the DNA that can alter imprint gene expression, thereby resulting in a multitude of genetic diseases including cancer and neuro-behavioral disorders. This PA will expire 3 years from the first receipt date. That is, the final receipt date will be October 1, 2002. The NIH Grants policy statement apply to these awards. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS- led national activity for setting priority areas. This PA, EXPLORATORY GRANTS FOR GENOMIC IMPRINTING AND ENVIRONMENTAL DISEASE SUSCEPTIBILITY, is related to the priority area of environmental health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001- 00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800), or at http://odphp.osophs.dhhs.gov/pubs/hp2000 ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, 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. Applications may be from a single institution or may include arrangements with one or more institutions (e.g., consortia, if appropriate). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Support of this program will be through the National Institutes of Health (NIH) exploratory/developmental grant (R21) mechanism. Applicants will be responsible for the planning, direction, and execution of the proposed project. All PHS and NIH grants policies will apply to applications received and awards made in response to this PA. Applicants may request up to $100,000 per year in direct costs. The total project period for an application submitted in response to this PA may not exceed 2 years. These grants are non-renewable and continuation of projects developed under this program will be through the traditional unsolicited investigator initiated grant program. Amended applications will be accepted. Though the size of the award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/ developmental project. 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 Applications will request direct costs in $25,000 modules. A feature of the modular grant is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information is required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. RESEARCH OBJECTIVES Background The NIEHS supports basic research and prevention/intervention studies related to environmental health through research project grants. Historically, this research has emphasized evaluation of health risks or disease outcomes, rather than the fundamental mechanisms of disease etiology. However, with the exception of Small Research Grants (R03), primarily targeted to new or previously unfunded areas of investigations, it has been difficult for scientists to obtain funding for hypothesis development, methods development, new intervention approaches, or feasibility studies. It is expected that these R21 grants will serve as a basis for planning future mechanistic research project grant applications (R01). This PA, therefore, is intended to stimulate innovative approaches to further enhance genomic imprinting research, and specifically, to better understand the role of the environment in its modulation. Because the exploratory grant mechanism is designed to support innovative ideas, preliminary data as evidence of feasibility are NOT required. However, the applicant does have the responsibility for developing a sound research plan with a strong theoretical or empirical basis. Originality of the approach and potential significance of the proposed research are major considerations in the evaluation. Research Goals and Scope Although two copies of autosomal genes are present in everybody, in some instances only one copy is expressed. Surprisingly, it was found that the expressed copy was dictated by whether that particular allele was inherited from the father or the mother, a phenomenon termed imprinting. Genomic imprinting in humans is a recently recognized phenomenon, but it has already been demonstrated to have a role in several developmental and pathological processes. There are now more than 25 identified imprinted genes, and estimates based on mouse models indicate that as many as 100 to 200 may exist. We do not yet have a clear understanding of their function in normal development, though it appears that some imprinted genes are involved in fetal and placental growth, cell proliferation, and adult behavior. Imprinting and X chromosome-inactivation, both assure that normally only one of the two identical gene sequences will be expressed in the cell. Genomic imprinting is not a cause of human disease itself, but rather is a normal process which, when disrupted, causes human disease. The origin of chromosomal deletions and nondisjunction, which cause such imprinting disruptions (much as they cause other human disorders when they affect non-imprinted genes), is unknown despite many years of research. Efforts are now focused on identification of intrinsic structural characteristics of the DNA at the breakpoint sites, since this may provide insight into the origin of chromosomal deletions, especially those that seem to recur with some frequency, such as in Prader-Willi and Angelman syndromes. For example, recently, a 50-60 KB complex repeat has been found to occur in the vicinity of the common PWS/AS breakpoints, but not elsewhere in the genome, suggesting that this structure may predispose to homologous recombination. Earlier studies identified an increased likelihood of occupational hydrocarbon exposure among fathers giving birth to children with Prader-Willi syndrome when compared with published general population figures, suggesting that this may be a factor predisposing to chromosomal deletion in PWS. Indeed environmental factors predisposing to chromosomal breakage at structural predisposed sites remain a fertile ground for future research efforts. Further search for imprinted genes, as well as for candidate genes associated with specific defects of genomic imprinting, are likely to lead to insights into the reason that this mechanism of control of gene expression arose. It will also provide insight into the pathogenesis of disorders resulting from abnormalities in imprinting. Genomic imprinting modulates gene expression by providing the means to turn specific alleles of a gene on or off in a parent-of-origin dependent manner. The imprint silences the allele from one parent. However, parental imprinting is not an all-or-none phenomenon. It is by design an inherently unstable mechanism of gene regulation. Both genetic and environmental factors can affect the imprinting process and alter the level of expression of imprinting genes. In addition to developmental and tissue-specific variation, imprinting can also be polymorphic among individuals. DNA methylation and chromosome structure regulate genomic imprinting. Thus, environmental factors capable of causing epigenetic changes in the DNA can potentially alter imprint gene expression and result in genetic diseases that include cancer and behavioral disorders. Some of the questions that need to be answered include: 1. Can environmental agents alter gene expression by altering chromatin structure? 2. How permanent are these changes? 3. Can environmental agents alter the imprinting status of the genome? 4. Can environmental agents alter the developmental program of imprinting? 5. If environmental agents induce changes in imprinting patterns, are these associated with human diseases or disorders? INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994 available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning policy. 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/funding/children/children.htm APPLICATION PROCEDURES 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 PHS 398 Form (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov. For those applicants with internet access, the 398 kit may be found at http://grants.nih.gov/grants/funding/phs398/forms_toc.html Applicants are strongly encouraged to contact the program staff listed under INQUIRIES with any questions regarding their proposed project and the goals of this PA. 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. 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, to indicate Modular Direct Costs (in $25,000 increments) and Total Costs [Modular 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 page 4 of the PHS 398 Form (rev 4/98). 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 page 5 of the PHS 398 Form. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (For sample pages, see http://grants.nih.gov/grants/funding/modular/modular.htm). At the top of the page, enter the total direct costs requested for each year. This is not a form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals or 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 domestic or foreign. 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 3 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. It is important to identify all appropriate exclusions that were used 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. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS PA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. The PA 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 five signed, exact, single-sided 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) Applications will be accepted on the standard application receipt dates for investigator initiated research as indicated in the PHS 398 directions. The Center for Scientific Review (CSR) will not accept any application in response to this PA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second-level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance human health. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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 will also 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. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority INQUIRIES Inquiries concerning this PA are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding general programmatic issues to: Jose M. Velazquez, Ph.D. Scientific Program Administrator Chemical Exposures and Molecular Biology Branch Office of Program Development Division of Extramural Research and Training National Institute of Environmental Health Sciences Post Office Box 12233 (EC-21) Research Triangle Park, NC 27709 Telephone: (919) 541-4998 Fax: (919) 316-4606 E mail: velazqu1@niehs.nih.gov Direct inquiries regarding fiscal matters to: Ms. Laura Williams-Boyd Grants Management Specialist Grants Management Branch (EC-22) Office of Program Operations Division of Extramural Research and Training National Institute of Environmental Health Sciences Post Office Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-7629 Fax: (919) 541-2860 Email: Willia27@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.113. Awards are made under authorization of the 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 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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