MECHANISMS OF ENVIRONMENTAL OXIDATIVE STRESS AND DIETARY MODULATION Release Date: February 7, 2001 RFA: RFA-ES-01-004 National Institute of Environmental Health Sciences ( National Institute of Diabetes and Digestive and Kidney Diseases ( Letter of Intent Receipt Date: March 1, 2001 Application Receipt Date: April 16, 2001 PURPOSE The purpose of this Request For Applications (RFA) is to stimulate and support investigator-initiated research that will provide data to enhance our understanding of the role of dietary modulators and nutritional factors in the molecular control of reactive oxygen species in initiation and progression of environmentally induced disease processes. Recent evidence has shown the importance of nutrition in delaying the aging process and in protecting against many degenerative and chronic diseases. Our growth in knowledge of reactive oxygen species, oxidative damage, and the role that nutritional antioxidants play in protection from this damage suggests that factors in our diet can be effective in preventing or retarding the disease process. In response to these findings, the National Institute of Environmental Health Sciences (NIEHS) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) seek to stimulate research efforts aimed at enhancing our understanding of the role of nutrition and diet in modifying, positively or negatively, environmentally induced oxidative damage in the progression of disease. Results of such investigations should clarify the cellular and molecular mechanisms by which nutritional agents alter oxidative balance and thereby prevent disease. 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 Application (RFA), Mechanisms of Oxidative Stress and Dietary Modulation, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at 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. Foreign institutions are not eligible for RO3 grants. 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) small grants program (RO3) 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 two years. This RFA is a one-time solicitation. The anticipated award date is September 2001. FUNDS AVAILABLE The National Institute of Environmental Health Sciences (NIEHS) intends to commit up to $1.5 million in FY 2001 to fund approximately 20 new grants in response to this RFA. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) intends to commit $150,000 to fund approximately two applications relevant to diseases within the mission of NIDDK. NIDDK has a particular interest in the role of antioxidants in the prevention of diabetic complications. An applicant may request a project period of up to two years and a budget for direct costs of up to $50,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIEHS and NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background The mission of the NIEHS is to reduce the burden of environmentally associated diseases by defining how environmental exposures affect our health, how individuals differ in their susceptibility to these exposures, and how these susceptibilities change with age. Environmental health comprises those aspects of human health, including quality of life, that are determined by physical (ex: radiation), chemical (ex: pesticides), biological (ex: diet), social and psychosocial factors (ex: socioeconomic status). It also refers to the theory and practice of assessing, correcting, controlling and preventing those factors in the environment that can potentially affect adversely the health of present and future generations. Therefore, a major focus of NIEHS is in the area of preventive research and medicine. The most effective way to prevent disease is to understand the cause of an illness and then change the condition that permits it to occur. Studies have shown that proper diet and nutrition play a major role in an individual’s susceptibility to environmental agents. For example, it has been shown that folic acid deficiency may be a risk factor for the development of cancer. Folate deficiency leads to chromosome breaks due to deficient methylation of cUMP to dTMP and subsequent incorporation of uracil into DNA. Increasing folate in the diet inhibits DNA uracil levels and chromosome breaks, thereby preventing disease. Additional research has suggested that oxidative stress may contribute to diseases associated with environmental exposures such as Parkinson’s disease. These examples serve to highlight the importance of understanding the mechanisms by which nutritional factors influence environmentally induced oxidative damage. Reactive Oxygen Species (ROS) are produced during normal cellular function and are generated as by-products of cellular metabolism, primarily in the mitochondria. ROS include hydroxyl radicals (OH), superoxide anion (O2-), hydrogen peroxide (H2O2) and nitric oxide (NO). Under normal conditions, cells have well-developed antioxidant systems that minimize the perturbations caused by ROS. However, when ROS generation is increased to an extent that overcomes the cellular antioxidants, then oxidative stress results. Therefore, oxidative stress may be viewed as a continuous battle between inducers (pro-oxidants) and protective factors (antioxidants). Because ROS are partially reduced products of oxygen, they have a high chemical reactivity with other bio-macromolecules that may lead to lipid peroxidation, and oxidation of DNA, RNA and proteins. Due to this reactivity, oxidative stress is thought to play an important contributory role in the pathogenesis of numerous degenerative and chronic diseases. Antioxidants are substances that either directly or indirectly protect cells against the adverse effects of xenobiotics, toxicants, drugs, and carcinogens. Antioxidants can be divided into three categories: 1. Dietary (nutritional) antioxidants are low molecular weight compounds ingested in the diet such as vitamin C, vitamin E, the carotenoids, flavonoids, other plant phenolics and wine phenolics. 2. Intrinsic molecules such as glutathione, albumin, bilirubin and uric acid. 3. Enzymes that specifically metabolize ROS precursors, such as catalase, superoxide dismutase (SOD), glutathione peroxidase, and peroxiredoxins. Many epidemiological studies have shown a link between diet and/or nutrition and the development of disease. Studies have shown that a low consumption of fruits and vegetables have been associated with a high risk of cancer, cardiovascular disease, type 2 diabetes and other chronic diseases. Although epidemiological studies have shown this link, the understanding of the mechanism for the efficacy of fruits and vegetables is unclear. Fruits and vegetables are a rich source of a variety of micronutrients, including vitamins, trace minerals such as selenium, dietary fiber and many other classes of biologically active compounds. Several of these micronutrients have been shown to prevent the disease process by serving as antioxidants in stopping the free radical chain of events. To inhibit free radical generation, dietary antioxidants can minimize oxidative damage by: 1. Inhibiting initiation by blocking cellular free radical generators. 2. Scavenging peroxyl radicals to prevent their propagation by converting them to hydroperoxides, which are then disposed of by glutathione peroxidase. 3. Repairing long-lived biological radicals before they are converted into stable products. 4. Inhibiting cellular expression of a mutagenic lesion. 5. Inducing apoptosis of damage cells. 6. Inducing and assisting enzymatic antioxidants and detoxifying agents. There is scientific evidence that antioxidants and other micronutrients in the diet may play a major role in preventing or retarding oxidative stress in disease. Since endogenous antioxidant defenses are not 100 percent efficient, dietary antioxidants may be important in diminishing the cumulative effects of oxidative damage over the long human life-span. This influence may account for some of the beneficial effects of fruits, grains, and vegetables. Studies have also shown that animals on low caloric diets tend to have lower oxidative damage to DNA, proteins and lipids and they also have higher levels of protective catalase activity. In addition, some diseases, such as diabetes, have been associated with decreased levels of endogenous antioxidants, such observations could potentially increase the importance of nutrients as a source of antioxidants in affected individuals. Combined, these studies indicate that proper nutrition and caloric restriction may improve cells ability to remove reactive substances and damage to macromolecules, thereby protecting against many environmentally induced diseases. Epidemiological studies have also shown that inter-individual variations due to genetic polymorphisms (ex: single nucleotide polymorphisms (SNP S)) can contribute to an individual’s susceptibility to ROS damage in various tissues. Therefore, it is important to understand the role of SNP’s and nutrition in human health and disease. An example of such studies is the manganese superoxide dismutase polymorphism linked to increased breast cancer risk in premenopausal women. This study observed that breast cancer risk was greatest among women who consumed lower amounts of dietary antioxidants and was minimal among women who were high consumers of dietary antioxidants. This observation suggests that a diet rich in sources of antioxidants may minimize the effects of the manganese superoxide dismutase polymorphism. Despite these recent advances in nutritional research to understand the role of nutrition in the prevention of disease, there is an inadequate knowledge base regarding the underlying molecular mechanisms by which micronutrients exert their effects in altering the disease process. The NIEHS and NIDDK are interested in studying nutritional components of disease risks and understanding the molecular basis of nutrition. Therefore, this RFA specifically aims to support studies that will better define the molecular mechanisms by which dietary factors inhibit environmentally induced oxidative damage. Research Objectives: The objectives of this RFA are to encourage and support mechanistically based research designed to characterize the linkage between diet, nutrition and environmentally induced oxidative stress (damage) and disease. Emphasis should be placed on developing the preliminary data that could lead to larger scale research project grants. Examples of relevant areas of investigation that examine the influence of dietary pro-oxidants and antioxidants on oxidative damage may include, but are not limited to: o Susceptibility of different cellular systems to environmentally induced in vitro and in vivo oxidation as a measure of the endogenous antioxidant defense system. o The capability of dietary antioxidants to inhibit or scavenge radical production in cells and tissues under various exposures to environmental agents, pro-oxidants and antioxidants. o The mechanism of action of proteins and transcription factors involved in ROS regulatory pathways as inducers of oxidative stress. o Molecular mechanisms by which dietary antioxidants, xenobiotics, environmental toxicants, and carcinogens interact to alter gene expression and structure/activity relationships of detoxifying enzymes. o The identification of cytosolic factors that serve as oxidative sensors within cells and their mechanism of action, and their control by diet or nutritional supplements. o Molecular mechanisms that control ROS homeostasis (ex: NF kappa B, Ap-1, hypoxia inducible factor-1) and their regulation by diet or nutritional supplements. o The role of ROS, antioxidant enzymes and cellular redox changes in transcriptional regulation, cell cycle control and signaling events in apoptosis. o The role of single nucleotide polymorphisms in understanding mechanisms and risk factors in diet and prevention of environmentally induced disease. o Mechanisms by which caloric restriction decreases production of ROS. o Mechanisms of oxidant induced alterations in lipid peroxidation, protein alkylation and DNA modification (ex: hypermethylation and hypomethylation). Projects may utilize a variety of scientific approaches, including in vitro studies, animal models or epidemiology. All projects must examine the interaction of dietary pro-oxidants and antioxidants and environmentally induced oxidative damage which may lead to disease. Projects lacking an examination of nutritional factors, which may include nutritional supplements, will be considered non-responsive and returned to the applicant without review. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (, a complete copy of the updated Guidelines are available at The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: 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 by March 1,2001 that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIEHS staff to estimate the potential review workload and plan the review. The letter of intent is to be e-mailed or mailed to: Ethel B. Jackson, D.D.S. Chief, Scientific Review Branch Office of Program Operations Division of Extramural Research and Training National Institute of Environmental Health Sciences 111 T.W. Alexander Drive P.O. Box 12233 Research Triangle Park, N.C. 27709 Phone (919) 541-7846 Fax (919) 541-2503 email: 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 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, email: THE FOLLOWING ARE SUPPLEMENTAL INSTRUCTIONS: o Only one small grant application may be submitted by a Principal Investigator. o The applicant must be explicit in describing the proposed interface between nutrition and oxidative damage. 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. However, if a color or glossy figure is essential for full consideration of your application, this material only can be included as an appendix. o The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The sample RFA label available at: has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Ethel B. Jackson, D.D.S. Chief, Scientific Review Branch Division of Extramural Research and Training Office of Program Operations National Institute of Environmental Health Sciences 111 T.W. Alexander Drive P.O. Box 12233 Research Triangle Park, N.C. 27709 Phone (919) 541-7846 Fax (919) 541-2503 email: Applications must be post marked by the application receipt date listed in the heading of this RFA. 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 responsiveness by the NIEHS and NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIEHS in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score. 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 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. SCHEDULE Letter of Intent Receipt Date: March 1, 2001 Application Receipt Date: April 16, 2001 Peer Review Date: June, 2001 Earliest Anticipated Start Date: September, 2001 AWARD CRITERIA Award 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 Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Joan P. Packenham, Ph.D. Scientific Program Administrator Chemical Exposures and Molecular Biology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD EC-21 111 T.W. Alexander Drive Research Triangle Park, NC 27709 Telephone: (919)541-4528 Fax: (919)306-4606 Email: Barbara Linder, M.D., Ph.D. Program Director Clinical Endocrinology and Diabetes Complications Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Rm. 699 Bethesda, MD 20892-5640 Telephone: (301) 594-0021 Fax: (301) 480-3505 Email: Direct inquiries regarding review issues to: Ethel B. Jackson, D.D.S. Director, Scientific Review Branch National Institute of Environmental Health Sciences Scientific Review Branch Division of Extramural Research and Training P.O. Box 12233, MD EC-30 111 T.W. Alexander Drive Research Triangle Park, NC 27709 Phone (919) 541-7846 Fax (919) 541-2503 email: Direct inquiries regarding fiscal matters to: Carolyn Winters Grants Management Specialist Grants Management Branch Office of Program Operations Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD EC-30 111 T.W. Alexander Drive Research Triangle Park, NC 27709 Telephone: (919)541-7823 FAX: (919)541-2860 Email: Charlette Kenley Grants Management Specialist Division of Extramural Activities National Institute of Diabetes, Endocrinology and Metabolic Diseases 6707 Democracy Blvd., Rm. 640 Bethesda, MD 20892-5456 Telephone: (301) 594-8847 Fax: (301) 480-3504 Email: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.113 and 93.115,and 93.847. 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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