Full Text ES-97-002 LINKING ENVIRONMENTAL AGENTS, OXIDATIVE DAMAGE AND DISEASE NIH GUIDE, Volume 26, Number 11, April 4, 1997 RFA: ES-97-002 P.T. 34 Keywords: Environmental Effects 0705048 Pathogenesis National Institute of Environmental Health Sciences National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: May 9, 1997 Application Receipt Date: June 12, 1997 PURPOSE The National Institute of Environmental Health Sciences (NIEHS) supports research to identify the role of environmental agents in perturbations of normal physiologic processes leading to human dysfunction and disease of all types. The National Heart, Lung, and Blood Institute (NHLBI) supports research to investigate the pathologic mechanisms in acute and chronic pulmonary diseases, and cardiovascular diseases. It has been shown that reactive oxygen species (ROS) are formed, and play a role, in the toxic manifestations of many xenobiotics. There are also preliminary data to show that oxidative damage may initiate or exacerbate specific diseases or dysfunctions including cardiovascular and pulmonary disease. However, in most cases no relationships have been developed to demonstrate that environmental agents act via oxidative damage, or if diseases and dysfunctions are the result of oxidative damage stimulated by such agents. Therefore, the goals of this Request for Applications (RFA) are to encourage research to develop biomarkers of oxidative damage and to focus on the oxidative stress mechanism as a result of exposure to injurious agents and the etiology, initiation or exacerbation of human disease including direct or indirect roles for ROS in pulmonary and cardiovascular disease. It is anticipated that research projects generated as a result of this RFA will stimulate scientists to explore oxidative damage as a critical pathway in pulmonary and cardiovascular disease as well as diseases induced by environmental agents in order to develop hypothesis-based research needed to establish cause and effect relationships. 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, "Linking Environmental Agents, Oxidative Damage and Disease" is related to the priority area of environmental health, unintentional injuries, heart disease and stroke, and chronic disabling diseases. 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). 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 or local governments and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. Submission of an application precludes concurrent submission of a regular research grant application (R01 or R29) containing the same research proposal. In addition, small grant research support may not be used to supplement research projects currently supported by Federal or non-Federal funds or to provide interim support for projects under review by the Public Health Service. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Small Grants Program (R03) awards. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The requested costs and project period will be $50,000 (direct cost) for a maximum of one year. Small grants are not renewable. FUNDS AVAILABLE The total estimated funds available for support of this Small Grants Program is $1,200,000, which will support 16-18 awards. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for within the financial plans of the NIEHS and the NHLBI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Reactive oxygen species (ROS) include the superoxide anion (O2), hydrogen peroxide (H2O2), the hydroxyl radical (OH), lipid peroxides, nitric oxide (NO), singlet oxygen (O21), ozone (O3), and hypochlorous acid (HOCl). They are partially reduced products of oxygen; some are free radicals. They are known to cause oxidation of membrane phospholipids; lipid peroxidation; protein damage, including cleavage of amino acid bonds; DNA strand breaks, or base modifications leading to point mutations; inhibition of RNA and protein synthesis; protein cross-linking; impaired maintenance of membrane ion gradients; and depletion of cellular levels of ATP, leading to cellular dysfunction and eventually to disease. Reactive oxygen species are continuously produced in living cells naturally as a result of leakage of electrons on the electron transport chain in mitochondria. In addition, they can be produced in cells by various enzymatic mechanisms (xanthine oxidase, cytochrome P450, etc.), auto-oxidation of small molecules (catecholamines, etc), or in response to xenobiotics, exogenous environmental exposures, ischemia, or inflammatory stimuli. Cells have well-developed antioxidant systems to protect themselves from ROS. These include low molecular-weight antioxidants like ascorbic acid; alpha-tocopherol and glutathione; and antioxidant enzymes such as catalase, glutathione peroxidases and superoxide dismutases (SODs). In addition, cells have the ability to repair damage caused by ROS (DNA repair enzymes, proteases, lipases, etc.). Many environmental and industrial agents such as tobacco smoke, stored food products, dietary trace element additives, some metals, pesticides, ozone, NO2, and TCDD will provoke an oxidative stress response, overwhelm antioxidant defense systems and result in oxidative damage to tissues. Transition metals including iron, copper, chromium, and vanadium undergo redox cycling that can result in generation of ROS. Cadmium, mercury and nickel deplete glutathione resulting in increased levels of ROS leading to lipid peroxidation, DNA damage, protein cross linking and altered calcium homeostasis. The toxicities produced by these metals usually involve tissue damage in the kidneys, liver or central nervous system. Bacterial products, such as endotoxin (lipopolysaccharide), and trauma can also induce production of reactive oxygen species and result in tissue damage and organ injury. In 1996 NIEHS held a workshop entitled, "Measurement of Oxidative Stress in Humans" to stimulate interaction between basic scientists and epidemiologists. The recommendations from this workshop emphasized the importance of the development, standardization and validation of biomarkers of oxidative stress in humans and the collaboration between basic scientists and epidemiologists in this process. In 1996, the NHLBI convened a Special Emphasis Panel of investigators in the areas of acute lung injury, interstitial pulmonary disease, and lung development to stimulate discussion and solicit recommendations for areas of research to be emphasized in the future. They recommended that generation of ROS, mechanisms of tissue injury, and mechanisms by which ROS generation is regulated in the lung should be considered areas of high interest to the NHLBI. This RFA has been developed, in part, to foster implementation of these recommendations. Research Goals The goals and scope of this RFA are to encourage and support mechanistically-based research designed to establish the linkage among three events: exposure to an environmental agent tested at environmentally relevant concentrations, resultant oxidative damage and the initiation or exacerbation of diseases. Laboratory research is encouraged that will increase our understanding of the oxidative stress pathways of damage in relation to environmentally-induced disease. Emphasis should be placed on developing the preliminary data that will lead to the development of cause and effect relationships among environmental agents, oxidative damage and the etiology of disease. The development of new biomarkers of oxidative damage in human populations is also encouraged. This includes research which will assess intra individual variability, sensitivity and specificity of these biomarkers. Collaborations between laboratory scientists and epidemiologists in the development and validation of biomarkers of oxidative stress in humans is strongly encouraged. Diseases of specific interest for this program include (but are not limited to): reproductive; immune; lung; cardiovascular; neural; as well as gastrointestinal disorders; osteoporosis and other bone diseases; renal diseases; and abnormalities in growth and development. Experiments using animal models or human tissue and/or cell lines would be appropriate. Biomarkers of ROS damage can be developed in animal models or human specimens but must be validated in exposed human populations. Environmentally-relevant concentrations using dose-response data are encouraged. The effect of age and the timing of exposure relative to the toxicity or effect should also be included as part of the experimental design. The purpose of this RFA is to expand data on non-cancer health endpoints. Therefore, research on the role of ROS on the initiation or progression of cancers of any type will be considered non-responsive. In addition, areas of science in which there are sufficient preliminary data that would support the submission of a regular research project grant application do not qualify under this RFA. ANIMAL WELFARE CONSIDERATIONS Investigators are encouraged to consider alternative methods and approaches in their research applications that do not require the use of whole animals, that use alternative species such as non-mammals or invertebrates, that reduce the number of animals required, and that incorporate refinements to procedures that will result in the elimination or further minimization of pain and distress to animals. 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 58 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 May 9, 1997, 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 subsequent application, the information that it contains allows NIEHS staff to estimate the potential 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, Building 17, Room 1716 Research Triangle Park, NC 27709-2233 Telephone: (19) 541-7846 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. Applications 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 301/435-0714, email: ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed under inquiries. THE FOLLOWING ARE SUPPLEMENTAL INSTRUCTIONS: o Only one small grant application may be submitted by a principal investigator. o A detailed budget should be completed as instructed on Page II of the U.S. Department of Health and Human Services Public Health Service Grant Application (PHS 398, rev. 5/95). The budget may not exceed $50,000 direct costs. Equipment will be limited to $5,000. Indirect costs will be awarded at the grantee's current negotiated indirect cost rate at the time of the award. o The applicant must be explicit in describing either the proposed interface between an environmentally relevant agent, oxidative stress and the induction or exacerbation of a specific disease or dysfunction or the development of biomarkers of oxidative damage in humans that could be used to develop the relationship between ROS and diseases/dysfunctions. Background information must suggest, or at least not preclude, a possible interaction between these three parameters or discuss the potential relationship of ROS to the pathogenic mechanisms in pulmonary or cardiovascular diseases. o Since this award is to support pilot studies, preliminary data are not required except to indicate the expertise of the principal investigator to carry out the proposed studies. o The research plan (aims, background and significance, preliminary data and experimental design and methods) is limited to 10 pages. Tables and figures are included in the 10-page limitation. Applications that exceed page limitation or PHS requirements for type, size and margins (see PHS 398 directions) will be returned to the investigator. o Do not submit an appendix. The RFA label available in the PHS 398 application kit, (rev. 5/95), 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 the review. In addition, the RFA title and number must be typed on line two 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: DIVISION OF RESEARCH GRANTS 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, Building 17, Room 1716 Research Triangle Park, NC 27709-2233 If these two additional copies are not forwarded to Dr. Jackson, it will adversely affect the review of the grant application: Applications must be received by June 12, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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 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 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 applications under review, will be discussed and assigned a priority score. Review Criteria o Scientific, technical, or medical significance and originality of proposed research as it relates to contributions to knowledge of health outcomes as a result of exposure to environmental agents; o feasibility of the proposed research; o appropriateness of the proposed budget and adequacy of the experimental approach and methodology proposed to carry out the research; o "high risk" with likelihood of "high gain;" o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o linkage of an environmental agent, oxidative stress/damage and initiation or exacerbation of a specific non cancer disease/dysfunction; o plausibility of the biological mechanism suggested linking the environmental exposure, oxidative damage and the etiology of disease; o examination of the role for reactive oxygen species in the pathogenesis of pulmonary or cardiovascular disease; and o availability of resources necessary to perform the research. AWARD CRITERIA The anticipated date of award is September 1997 pending availability of funds. 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 announcement. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcomed. Direct inquiries regarding programmatic issues to: Jerrold J. Heindel, Ph.D. Organs and Systems Toxicology Branch National Institute of Environmental Health Sciences P.O. Box 12233, MD 3-02 111 T. W. Alexander Drive, Building 3, Room 316 Research Triangle Park, NC 27709-2233 Telephone: (919) 541-0781 FAX: (919) 541-2843 Email: heindelj@niehs.nih.gov Gwen W. Collman, Ph.D. Chemical Exposures and Molecular Biology Branch National Institute of Environmental Health Sciences P.O. Box 12233, MD 3-04 111 T.W. Alexander Drive, Building 3, Room 306 Research Triangle Park, NC 27709-2233 Telephone: (919) 541-4500 FAX: (919) 541-2843 Email: collman@niehs.nih.gov Robert A. Musson, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10018, MSC 7952 Bethesda, MD 20892 Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: rmusson@nih.gov Momtaz Wassef, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung and Blood Institute 6701 Rockledge Drive, Room 10188, MSC 7956 Bethesda, MD 20892 Telephone: (301) 435-0550 FAX: (301) 480-2858 Email: wassefm@gwgate.nhlbi.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, MD 2-01 111 T.W. Alexander Drive, Building 2, Room 203B Research Triangle Park, NC 27709-2233 Telephone: (919) 541-7628 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov Inquiries to other institutes with similar R03 Programs: The National Institute on Deafness and other Communication Disorders (NIDCD) is interested in research that is directed towards oxidative damage to the systems of hearing, balance, smell and taste. The NIDCD has an R03 Program that can be found on the NIH Home Page as PAR-97-012 under grants and contracts. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.113 and 93.115. 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, 42 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 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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