Full Text ES-97-001 MODULATION BY GROWTH FACTORS AND SIGNAL TRANSDUCTION PATHWAYS OF ENVIRONMENTALLY-INDUCED DISEASE/DYSFUNCTION NIH GUIDE, Volume 26, Number 4, February 7, 1997 RFA: ES-97-001 P.T. 34 Keywords: Growth Factors Environmental Effects 0765014 National Institute of Environmental Health Sciences Letter of Intent Receipt Date: April 18, 1997 Application Receipt Date: May 16, 1997 PURPOSE Historically, 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. 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. The mechanistic knowledge of environmental agent impact on the genome exists, either in actuality or conceptually; therefore, through the coupling with recent advances in molecular biology, the capability exists to intercede or modulate environmentally-induced toxic effects. Accordingly, the objective of this Request for Applications (RFA) is to encourage innovative, mechanistically based research to elucidate how growth factors modulate environmentally induced altered gene functions; and conversely, how environmental agents alter or modulate the function of growth factors and the cellular signaling cascades. Information derived from these studies opens the possibility of developing therapeutic strategies to protect normal tissues from environmental toxicants. The NIEHS is the principal Federal funding agency that supports research examining human health consequences of exposure to physical and chemical toxicants in the environment. Research supported by NIEHS spans many disciplines, including toxicology, molecular and cellular biology, epidemiology, and clinical research. 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, "Modulation by Growth Factors and Signal Transduction Pathways of Environmentally Induced Disease/Dysfunction" 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, unit 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 requested direct costs submitted in response to this RFA may not exceed $200,000 per year. This RFA is a one-time solicitation. FUNDS AVAILABLE The total estimated funds available for the first year of support for the entire program are expected to be $1,500,000 in fiscal year 1997. Although the actual number may vary, the anticipated number of awards is four to six. 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 NIEHS has a continued commitment to stimulating research activities in the area of molecular intervention. Studies began in 1993 that focused on the use of molecular biomarkers as intermediate markers or endpoints to monitor the development, exacerbation or treatment of environmentally-induced diseases in clinical studies. These studies included biomarkers of inflammation in lung disease patients occupationally exposed to grain dust and endotoxins, immune markers in environmentally-induced asthma, biomarkers of dioxin-related compounds in humans and animals, molecular markers of response in beryllium-induced lung disease, and the development of markers to be used to measure success in interventional studies of lead in adults. As the results from these and other studies unfold, they will begin to have an impact on the Institute's research strategy to intervene at the molecular level in environmentally induced disease/dysfunction. Because of the diversity of this research area, this is the second such announcement; its focus is on the modulation of growth factors and by elements within signal transduction pathways in environmentally-induced altered gene function/expression. RESEARCH GOALS This RFA is part of a larger program, the "Molecular Interventions for Environmentally-Induced Disease Prevention". NIEHS's molecular intervention initiative is an element of the basic research agenda for Healthy People 2000, and is related to the national strategy for significantly improving the health of the Nation during the current decade. This initiative is aimed at encouraging investigator-initiated research to study basic molecular, biochemical, cellular, and structural mechanisms in the modulation of environmentally induced diseases or disorders. It is anticipated that these investigations will allow for innovative approaches in understanding the mechanism of the xenobiotic-induced molecular alterations in specific target cells and organs germaine to modulating gene expression, specifically by growth factors and/or signal transduction pathways. These studies would undoubtedly contribute to the development of specific therapies designed to amplify or decrease the susceptibility of individual cell types to specific environmental agents, and could form the basis for treatment of a variety of human diseases or disorders. Collaborative research efforts between investigators of the environmental health research community and molecular and structural biologists, molecular modeling scientists, and clinicians are especially encouraged. It is widely recognized that the response to cell damage is highly complex in its control and regulation, and includes direct interactions of xenobiotics with extracellular components, modulations of cell signaling pathways, transcriptional induction, cell cycle arrest, and effects on DNA structure and function. The following examples of research interest are not intended to be complete, and investigators may study these and other topics that meet the objectives of this RFA: o Studies targeted at determining how growth factors and their receptors modulate environmentally-induced altered gene function and structure; o Studies aimed at understanding how cellular signaling pathways modulate xenobiotic-induced gene expression; o Studies designed to improve our understanding of the correlation between chemical induction or suppression of programmed cell death or apoptosis, specifically as related to the use of this understanding in the potential modulation of such actions; o Research aimed at gaining a better understanding of the molecular and structural basis of tissue-specific and stage-specific gene expression of growth factors and their receptors following xenobiotic exposure, e.g., to identify and characterize factors that control cell specificity of gene expression and to utilize these cell- specific elements to explore the physiological consequences. To be responsive to this RFA, investigators should be able to illustrate how their proposed studies could contribute to the development of therapeutic strategies to prevent or ameliorate environmentally induced diseases or dysfunctions. SPECIAL REQUIREMENTS Annual meetings, to be held in Research Triangle Park, NC, are planned for the exchange of information among investigators. Applicants must budget travel costs associated with these meetings in their applications. LETTER OF INTENT Prospective applicants are asked to submit, by April 18, 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 consultants, the 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, Building 17, Room 1716 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. 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. 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: 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 Applications must be received by May 16, 1997. If an application is received after that date, the DRG 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 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 include the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. 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 RFA. Contact the program official listed under INQUIRIES regarding any changes in the schedule. Letter of Intent Receipt Date: April 18, 1997 Application Receipt Date: May 16, 1997 Initial Scientific Review: July 21-22, 1997 Advisory Council Review: September 1997 Anticipated Date of Funding: September 1997 REVIEW CONSIDERATIONS 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 National Environmental Health Sciences Advisory Council. Applications considered non-responsive to the RFA will be returned to the applicant for submission through the competitive mechanism. Review Criteria The following criteria will be considered: o scientific, technical, or medical significance and originality of the 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 key personnel; o availability of resources necessary to perform the research; and o appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is September 1997. 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 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. Chemical Exposures and Molecular Biology Branch National Institute of Environmental Health Sciences P.O. Box 12233, 104 Alexander Drive, MD-3-04 Research Triangle Park, NC 27709 Telephone: (919) 541-4998 FAX: (919) 541-4937 Email: velazqu1@niehs.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 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No.93.113, 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 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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