STRUCTURE-FUNCTION RELATIONSHIPS OF ENVIRONMENTALLY RELEVANT GENETIC VARIANTS Release Date: May 29, 1998 RFA: ES-98-007 P.T. National Institute of Environmental Health Sciences National Institute on Aging Letter of Intent Receipt Date: July 13, 1998 Application Receipt Date: August 13, 1998 PURPOSE The National Institute of Environmental Health Sciences (NIEHS) is the principal Federal funding agency that supports research focused on understanding the mechanisms for human health consequences of exposure to physical and chemical agents in the environment. As part of this mission, the NIEHS initiated the Environmental Genome Project (EGP) to establish how genetic polymorphisms influence susceptibility or resistance of individuals following exposure to environmental agents. By understanding how genetic polymorphisms in the general population affect individual responses to environmental agents, scientists can better predict health risks and policy makers will have a science-based framework for the development of environmental policies to protect susceptible individuals. The National Institute on Aging (NIA) is a cosponsor of this Request for Applications (RFA) and is interested in environmentally relevant polymorphisms in genes that also have implications for understanding individual susceptibility to aging. The objective of this RFA is to encourage multi-disciplinary projects to identify and characterize the gene products coded by allelic variants of environmental responsive genes (ERG). 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 RFA, Structure-Function Relationships of Environmentally Relevant Genetic Variants, 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 Superintended of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone (202) 512- 1800). 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 or local governments and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the NIH individual 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 three years. The direct cost per year for R01 grants may not exceed $500,000 without prior discussion with the program officer listed under the INQUIRIES. The anticipated award date is April 1, 1999. This RFA is a one-time solicitation. Unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to customary peer review procedures. For administrative reasons all applications received in response to this RFA will be assigned initially to NIEHS. After discussions between the participating Institutes and before review, applications will be reassigned to the Institute(s) that are programmatically most appropriate. Applications may receive dual assignments based on the established PHS guidelines. FUNDS AVAILABLE The funds available for the first year of support for this RFA are expected to be $3,500,000 in Fiscal Year 1999. Although the actual number may vary, the anticipated number of awards is seven to fifteen. The level of support is dependent on the receipt of sufficient number of applications of high scientific merit. Although this program is provided for within the financial plans of the NIEHS, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background The rapid increase in our understanding of molecular biology coupled with the technology and data emerging from the Human Genome Project offers the opportunity to exploit a new direction in environmental health science research. To this end, the NIEHS launched the Environmental Genome Project (EGP) to focus research on understanding the role of environmental responsive genes on human susceptibility to environmental agents. This RFA, which is an integral part of the EGP, is to encourage researchers to apply the new tools and technologies in molecular, biochemical, cellular, and structural biology to understand the biological significance of genetic polymorphisms in environmental responsive genes. Extensive background information on the NIEHS EGP is available at following URL: http://www.niehs.nih.gov/envgenom/home.htm and in the NIH GUIDE (January 9, 1998). Based on the extant data, the NIEHS is most interested in genes controlling the distribution and metabolism of toxicants, genes for DNA repair pathways, genes for the cell cycle control system, genes for cell death and differentiation, and genes for the signal transduction systems controlling the expression of the genes in the other categories. The NIEHS's EGP initiative is broader in scope and it is anticipated that the Project will include additional susceptibility genes as they are discovered. This RFA is intended to encourage fundamental studies to identify the biological impact of genetic polymorphisms in humans. Such data can be used as the basis for population-based epidemiological investigations for the identification of both the ERG alleles and the risk of disease resulting from exposure to environmental agents. Identification and Characterization of Polymorphisms Although many diseases may be caused by relatively rare mutations which result in total or near complete loss of biological functions, for many gene products, such as cellular enzymatic activities, it is clear now that common polymorphisms of the same genes may cause significant reduction of the cellular enzymatic activity, but to a level which does not lead to overt symptomology of disease. Polymorphisms of this type result in an apparently benign "pseudo-deficiency" of the metabolically important enzyme causing the individual to possess only minimal levels of the enzyme activity, rather than the excess of activity found in the majority of people. These individuals when exposed to certain environmental agents may experience a pathologic response at exposure levels that do not affect the general population as a result of the enzyme deficiency. For example, more than 60 genes code for the cytochrome P450 (CYP) enzyme superfamily, which is involved in the metabolism of almost all chemicals to which we are exposed in our internal and external environments. The CYP gene family codes for enzymes that are actors in a long pathway to detoxify and excrete xenobiotic chemicals (i.e., synthetic compounds foreign to living systems, such as drugs and insecticides). Looking specifically at the CYP2A6 genes in individuals of various ethnic backgrounds, investigators found two sequence variants. Variant one had a single amino acid change, and the heterozygous state resulted in a reduction of activity to about 50% to 80%. Homozygotes range from no activity up to 50% activity. A second variant has several differences in its sequence. There are no homozygotes for this variant, since it does not produce functional protein. This suggests that there is not an easy way to understand the correlation between variant sequence and phenotypic expression. In a similar fashion, DNA repair genes, discovered more than 30 years ago, are also important to toxicology. Several genes involved in different DNA repair pathways, such as base or nucleotide excision repair, have been cloned, mapped, and the cDNAs isolated. In many cases, the genomic sequences have been determined. Functions that have been ascribed to several of the DNA repair genes include helicase, endonuclease, polymerase, ligase, and other activities not fully understood but somehow involved in recombination and repair processes. One of the DNA repair genes -ERCC2- is interesting because it has variable expression in individuals and is associated with three different diseases. The most severe of these diseases is Xeroderma Pigmentosum type D, which is characterized by high sensitivity to UV light, high cancer incidence, and some neurological disorders. Another of the diseases, Cockayne's Syndrome, is characterized by slight photosensitivity and severe neurological defects but does not have a high cancer incidence. The third ERCC2 disease, trichothiodystrophy, presents a defect in the metabolism that causes brittleness of hair, pale skin, slight photosensitivity in about 50% of the patients, and some minor neurological defects. ERCC2 is one protein in a multi protein complex and is part of a transcription factor complex necessary for gene transcription into mRNA. Protein folding and interaction in the complex may affect the form and phenotype produced. To understand the functions of gene sequences, researchers can use a suite of techniques including standard biochemical approaches, structural approaches, or animal models such as knockout technologies in mice. In knockouts, a particular gene is disabled in the mouse, and any resulting changes in the animal are noted. Many novel human genes are being identified through comparisons with sequences from other species. In mouse-human comparisons, researchers use gene probes that will identify both human and mouse clones. For the DNA repair gene XRCC1, there are 17 exons in human and the same number of highly conserved exons in the mouse. Interestingly, some noncoding regions are also conserved. What function do these highly conserve, noncoding regions perform? Are they actually putative regulatory regions? As we have seen in the previous examples, understanding the biological significance of genetic polymorphisms is of utmost importance if we will ever be able to use DNA variation as an indicator of disease or susceptibility. More important, certain environmental factors might help trigger a disease onset. Therefore, individual variabilities in DNA sequences (polymorphims) of environmental responsive genes might help explain why some individuals in a population are susceptible to some environmental agents, and why others are resistant. Specific Research Goals The NIEHS and the NIA launching this EGP initiative because it is anticipated that data generated from the studies will allow for rapid developments of innovative approaches to elucidate the mechanisms of the xenobiotic-induced molecular alterations in specific target cells and organs. Collaborative research efforts between investigators in environmental health sciences and in molecular and structural biology, and/or molecular modeling disciplines are especially encouraged. Summary of major research objectives for this RFA: o biochemical and structural biological studies of the proteins coded by the allelic variants of candidate genes. These studies may include: characterization of enzyme activities, determination of protein folding and post-translational modifications, and cellular localization. o evaluation of the functional significance of single nucleotide polymorphisms or other allelic variations in candidate genes and their regulatory regions. o characterization of the molecular mechanisms controlling temporal and cellular regulation of expression of the allelic variants of a specific class of genes. The studies could include determination of RNA expression patterns that contain information about which sets of transcripts are expressed, at what level, in cell and tissue-specific manner at different stages of development, differentiation or time in the cell cycle. o functional genomic studies to assess the expression patterns and functions of these classes of environmental responsive genes at the organ/tissue/cell levels. o studies on protein-protein interactions to understand how a specific allelic variant of one class of gene interacts with other allelic variants of a different class of genes belonging to the same or different cellular pathways. SPECIAL REQUIREMENTS Investigators conducting biomedical research frequently develop unique research resources. The policy of the PHS is to make available to the public the results and accomplishments of the activities that it funds. All applications must adhere to the PHS policy for the distribution of unique research resources produced with PHS funding, which was published in the NIH Guide for Grants and Contracts, Vol. 25, No. 23, July 12, 1996, and is available at the following URL: http://grants.nih.gov/grants/guide/notice-files/not96-184.html. Post-Award Management Since it is anticipated that during the award period, technologies will improve and the rate of progress and focus of the projects may change, NIEHS plans to hold annual meetings of the grantees awarded through this RFA. Travel funds (up to $2,000 per year) for Principal Investigators to attend the annual meeting should be included in the requested travel budgets. The meeting will be coordinated by NIEHS Program officials to establish research priorities, review research progress and experimental difficulties, coordinate resource and data sharing, and discuss new technological developments applicable to this research program. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of 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. LETTER OF INTENT Prospective applicants are asked to submit, by July 13, 1998, 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, consultants, 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 subsequent application, the information that it contains is helpful in planning for the review of applications. It allows NIEHS staff to estimate the potential review work load and to avoid conflict of interest in the review. The letter of intent is to be sent to: Ethel B. Jackson, D.D.S. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, 111 T. W. Alexander Drive Research Triangle Park, NC 27709 Telephone: (919) 541-7826 FAX: (919) 541-2503 Email: jackson4@niehs.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institute of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435- 0714, Email: GRANTSINFO@NIH.GOV. If IRB or IACUC review is unavoidably delayed beyond submission of the application, a follow-up IRB certification and/or IACUC verification from an official signing for the applicant organization must be sent to and received by the Scientific Review Administrator of the Special Emphasis Panel by October 13, 1998. If IRB certification and/or IACUC verification is not received by October 13, 1998, the application will be considered incomplete and returned to the applicant. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the checklist, and three signed, clear, and 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) At the time of submission, two additional copies of the application must be sent to: Ethel B. Jackson, D.D.S. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O.Box 12233, 111 T. W. Alexander Drive, EC-24 Research Triangle Park, NC 27709 Applications must be received by August 13, 1998. If an application is received after that date, the Center for Scientific Review (CSR) may contact the applicant to determine whether it will be returned to the applicant or be reviewed with unsolicited applications for the next regular receipt date. The 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 include 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 CSR and responsiveness by the NIEHS. Incomplete and/or non-responsive to the RFA will be returned to the applicant for submission through the regular mechanisms. Applications that are complete and responsive to this RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIEHS in accordance with NIH peer review procedures. 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 appropriate National Advisory Council(s). 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 review, comments on the following aspects of the application will be made 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 the assignment of the overall score. o Significance: Does this study address an important problem? If the aims of the applications are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive the field of environmental health sciences? 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 project employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the project challenge current paradigms or develop new methodologies or substantially improve existing 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The reasonableness of the proposed budget and duration in relation to the proposed research. o The proposed plans for the distribution of data/materials generated by the research program. The application of creative and innovative (high risk/high impact) experimental approaches and the development of interactive strategies and collaborative teams to the research goals of this RFA are encouraged. Schedule The following is the schedule planned for this initiative. It should be noted that this schedule may be changed without notification due to factors that were unanticipated at the time of the announcement. Contact the program official below regarding any changes in the schedule. Letter of Intent Receipt Date: July 13, 1998 Application Receipt Date: August 13, 1998 Initial Scientific Review: October 21-23, 1998 Advisory Council Review: February 1-2, 1999 Anticipated Date of Award: April 1, 1999 AWARD CRITERIA The anticipated date of award is April 1, 1999. The following will be considered in making funding decisions: o quality of the proposed project as determined by peer review; o availability of funds; and o program balance among research areas of the RFA. INQUIRIES Written and telephone inquires concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcomed. Direct inquiries regarding programmatic issues to: Jose Velazquez, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, 111 Alexander Drive, MD EC-21 Research Triangle Park, NC 27709 Telephone: (919) 541-4998 FAX: (919) 541-4937 Email: velazqu1@niehs.nih.gov Huber Warner, Ph.D. Biology of Aging Program National Institute on Aging Bethesda, MD 20892 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: warnerh@exmur.nia.nih.gov Direct inquiries regarding fiscal matters to: Mr. David L. Mineo Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, 111 T.W. Alexander Drive, MD EC-22 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov Mr. Joseph Ellis Grants Management Office National Institute on Aging Gateway Building, Room 2N212 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-0066 Email: ellisj@exmur.nia.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.113, 93.114, and 93.15. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 43 USC 241 and 285) and administered under PHS Grants Policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of executive order 12372 or Health Systems Agency Review. The Public Health Service (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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