Full Text ES-92-03 MOLECULAR INTERVENTIONS FOR ENVIRONMENTALLY INDUCED DISEASE PREVENTION NIH GUIDE, Volume 21, Number 24, June 26, 1992 RFA: ES-92-03 P.T. 34 Keywords: Environmental Health Toxicology Biological Markers National Institute of Environmental Health Sciences Application Receipt Date: November 24, 1992 PURPOSE This RFA is the first of an anticipated series of solicitations in a broad research strategy to develop interventions at the molecular level for diseases with an environmental etiology. The current announcement focuses on the development and use of biomarkers to assess the effectiveness of intervention strategies. The elimination of toxic agents from the environment has dominated the field of prevention. Although the causes of certain human diseases are known, explicit preventive strategies still cannot be offered for avoidance of numerous risk factors associated with many types of disease sequelae. This is because there are unavoidable risk factors and inherent biostatistical and epidemiological limitations involved in the identification and interpretation of complex disease processes and potential low-risk hazards. Recently, control strategies involving a more mechanistic approach derived from chemical and biological research have received more emphasis. The objective of the strategies is eventual intervention through preventive/protection or other active means of modulating the risk factors. The National Institute of Environmental Health Sciences (NIEHS) has posed as one of its major goals of the 1990s the development of an effectual knowledge base that would equip clinicians to effectively treat people who are affected adversely by exposure to environmental agents. Accordingly, the NIEHS announces the availability of funds to support research efforts aimed at the development and clinical trial use of methods to prevent, modulate, or treat environmentally induced toxic effects. Such studies should provide new insight into the molecular bases for intervention to prevent or ameliorate environmentally induced diseases as well as associated alterations of biological processes related to toxicant exposures. The focus of this particular RFA is development and use of appropriate biomarkers to study effectiveness of potential intervention methods. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Health People 2000," a PHS-led national activity for setting priority areas. This RFA, Molecular Interventions for Environmentally Induced Disease Prevention, 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 "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington DC 20402-9325, telephone (202) 783-3238. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from minority individuals and women are encouraged. Foreign applicants are not eligible for the First Independent Research Support and Transition (FIRST) Award. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research grant (R01) and the FIRST Award (R29). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for applications submitted in response to the present RFA may not exceed five years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary NIH peer review procedures. FUNDS AVAILABLE The estimated funds (total costs) available for the first year of support for the entire program is $1.5 million. The expected number of awards is 8-12. 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 in the financial plans of the NIEHS, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES The ultimate goal and scope of this research program is the support of studies that will advance knowledge to diminish the risk of disease development. There are potentially many approaches that may have application to clinical solutions to ameliorate environmental toxicant effects and/or to intercede in disease pathways. Many diseases are thought of as multistage in process, while others are judged as multi-event. It is recognized that the environment may play a role in certain disease processes, although actual causative agents have been shown in only a few instances. Whereas cancer is a paradigm for multistage/multi-event processes, the reasonable and testable supposition is that there are other environmentally influenced chronic disease processes (e.g., atherosclerosis, Alzheimer's disease, and multiple sclerosis). Therefore, by identifying early, fundamental targets that could be control points of biochemical cascades of many subsequent events, a more effective and ubiquitous management of disease processes could be achieved. The focus of this RFA is on the development and use of biomarkers to assess the effectiveness of intervention studies. Biomarkers, as indicators of molecular and cellular events in biological systems, may allow epidemiologists and other health professionals to better examine the relationships between environmental hazards and human health effects. Biomarkers fall into three basic categories: biomarkers of dose, susceptibility, and effects. It is important to determine the mechanism of biomarker induction in humans and to help establish the utility of biomarkers as indicators of toxic exposure. Biomarkers of exposure can be used to quantify an individual's exposure to and uptake of environmental agents potentially related to disease. Biomarkers of internal dose can provide information not only on individual exposure and uptake, but also on metabolic activation and detoxification parameters that may be related to disease susceptibility. Such studies would also address the relationship of a biomarker to a disease process, i.e., does exposure lead to effect. As such, it is critical to link molecular intervention studies to related molecular epidemiology studies. The NIEHS is interested primarily in biomarkers correlated with non-cancer endpoints. Although applications related to cancer endpoints are acceptable, they will be weighted for programmatic balance. The following examples of areas of research interest are not intended to be complete, and investigators are encouraged to study these or other topics that meet the objectives of this announcement: Development of Biomarkers and Their Validation for Use in Exposure/Disease Relationships. o The knowledge of the mechanism(s) of biomarker induction in humans to help establish the utility as indicators of toxic exposure and to address the relationship to a disease process. The modulation of the levels of the biomarkers may correlate with the interventive/protective properties of an interceding agent. o Biomarkers of internal dose are of particular interest because they have the potential to detect enzymatic differences between individuals that may relate to disease susceptibility. It may be possible to modulate these enzymatic activities, e.g., inhibit metabolic activation processes or enhance detoxification processes, by interventions with specific agents, or by changes in exposure patterns or lifestyles. Biomarkers of internal dose can be used to assess the results of these interventions or changes in lifestyle. Use of Biomarkers in Prevention and Treatment Studies. o Molecular intervention studies related directly to epidemiology, especially in the development and use of molecular techniques for identifying affected individuals. Biomarkers have the potential to derive better risk models; intervention models with variable, yet predictable, risk may permit the validation of biomarker measurements to better extrapolate exposure to individual risk. Data from such studies should also lead to a better understanding of inter- and intra-individual variability. The scope of these studies may range from prevention of internal exposure to the toxic agent, to treatment of effects at the cellular and molecular level, to genetic control of the disease-regulating and -controlling events. Studies should be innovative, providing new insight into the molecular basis of biomarker induction and the concomitant modulation: (1) the molecular identification and quantification of exposure to environmental agents; (2) the amelioration of environmental agent-induced biological perturbations; and (3) the linkage of an environmental agent exposure to a specific disease or disease process. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, general and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Sections 1-4 of the Research Plan and summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and prevention strategies), diagnosis, or treatment of diseases, disorders or conditions, including, but not limited to, clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned to the applicant without review. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed and the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional business offices and from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 496-7441. The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the application. Failure to use this label may 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 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Mr. David L. Mineo Grants Management Officer Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences 104 T.W. Alexander Drive P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 Applications must be received by November 24, 1992. 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 announcement 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 Upon receipt, applications will be reviewed by NIH staff for completeness and responsiveness. Incomplete applications will be returned to the applicant without review. If the application is not responsive to the RFA, NIEHS staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Those applications judged to be competitive will undergo further scientific merit review. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NIEHS. The second level of review will be provided by the the National Advisory Environmental Health Sciences Council. Review criteria for this RFA are generally the same as those for unsolicited research grant applications. o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research. The subject of this RFA may overlap with interests of other Institutes, Centers, and Divisions (ICDs). Applicants will, therefore, be assigned according to extant PHS Referral Guidelines. If developing programs deal with clinical populations, applicants might wish to consider utilization of General Clinical Research Center (GCRC) facilities. More information on the GCRC program can be obtained from the National Center for Research Resources. AWARD CRITERIA The anticipated date of award is July 1, 1993. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: William A. Suk, Ph.D., M.P.H. Program Administrator Scientific Programs Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-0797 FAX: (919) 541-2843 Direct inquiries regarding fiscal matters to: Mr. David L. Mineo Grants Management Officer Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.894. 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. .
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