Full Text ES-96-006 THE USE OF TRANSGENIC MODEL SYSTEMS IN MOLECULAR TOXICOLOGY NIH GUIDE, Volume 25, Number 7, March 8, 1996 RFA: ES-96-006 P.T. 34 Keywords: Toxicology Animal Breed. & Facil., Scientific Environmental Effects National Institute of Environmental Health Sciences Letter of Intent Receipt Date: May 10, 1996 Application Receipt Date: June 10, 1996 PURPOSE A major goal of the National Institute of Environmental Health Sciences (NIEHS) is to foster research that will increase the knowledge of the diverse health effects of exposure to environmental agents. It is likely that many common diseases, including cancer, lung disease, neurodegenerative diseases, cardiovascular diseases, and developmental abnormalities or dysfunctions, have an environmental component. Further, there is a critical need for a thorough understanding of the action of environmental agents on human health at the genome level. Recent advances in molecular biology permit novel approaches for the identification of genes involved in environmentally associated diseases. Accordingly, the objective of this request for applications (RFA) is to encourage innovative, mechanistically based research using transgenic technologies to investigate the alterations of gene expression induced by environmental agents in specific target cells and organs, and to determine how this response varies at critical times during exposure. These studies would undoubtedly contribute to the development of specific therapies designed to enhance 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. 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, The Use of Transgenic Model Systems in Molecular Toxicology, 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 Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone (202) 5120-1800). 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 Only applications using the NIH individual research project grant (R01) award mechanism will be accepted in response to this RFA. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The requested direct costs for the R01 applications 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 is $1.5 million. The expected number of awards is six to eight. 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 impact of environmental agents on human health and well being has been clearly established. Exposure to environmental pollutants, because of their genotoxic and non-genotoxic potential, is likely to cause genetic and/or cellular perturbations leading to disease. Perhaps the best examples of gene environment interactions at the molecular level have come from studies of metabolic enzymes and DNA repair proteins. In the first case, the Phase I and Phase II enzymes have been identified as critical components in the oxidative metabolism of virtually all environmental chemicals. In addition to their role as a major detoxification system, it has become increasingly recognized that these enzymes are pivotal in many subcellular biosynthetic reactions and in regulating the effectors of many critical life processes, including cell growth, differentiation, programmed cell death or apoptosis, homeostasis, and neuroendocrine functions. Foreign chemicals can compete with the endogenous ligands, acting as either agonists or antagonists, in stimulating growth, perturbing differentiation, or evoking any numerous other signals that would lead to environmentally associated diseases. Somatic cell genetics has been used to identify genes necessary for the induction of these enzymes by toxic agents. For example, resistance to aryl hydrocarbon toxicity has been ascribed to several factors including: mutational alterations of the cytochrome P450 (CYP) genes, transcriptional deficiencies, mutations in regulatory sequences, mutations in other genes required for the normal translocation of the inducer receptor complex into the nucleus, and mutations of the AH receptor. Adding to this intricacy, it is known that the regulation and expression of the CYP genes varies as a function of age and sex. Striking tissue specific expression has also been detected. It is clear that this phenomenon is dependent on hormonal or diffusible factors, cell cell contact, and/or the differentiated states of cells in the intact animal. The CYP system represents an excellent tool to study gene environment interactions. However, it must be emphasized that numerous polymorphisms exists within other xenobiotic metabolizing enzyme families (e.g. glutathione transferase, UDP glucuronosyltransferases, paraoxonases, dehydrogenases, n acetyl transferases, and flavin containing dehydrogenases). It is the complex interplay of these and other enzyme families within any individual which will ultimately determine a particular response to a given chemical and potential for toxicity. The molecular details of how metabolic genes are activated by xenobiotic agents during development must await further characterization of these genes. The transgenic technologies now available allow for the determination of what role receptors, trans acting transcriptional control factors, and enhancer elements have in the altered expression of the genes. The DNA repair pathways represent another well studied system of gene environment interaction. Mammalian cells can regulate their DNA repair machinery in response to genotoxic damage. Thus, gene expression for many DNA repair proteins is increased in response to exposure of cells to genotoxic agents. In addition, the expression pattern of DNA repair proteins varies from tissue to tissue and with the differentiated state of the cells, perhaps reflecting variable capacity for DNA repair. It is believed that strategically regulating the transcriptional activation of these genes may allow for an enhancement of the cell s defense against DNA damaging agents. The plausible consequences of damage to the human genome from industrial and environmental chemicals is of serious concern, and hence the study of mutational phenomenon and modeling of cell susceptibility to such agents is of toxicological importance. In this context, a more thorough understanding of the cellular mechanisms which are involved in the processing of environmentally induced DNA damage is needed. The availability of the technology to produce whole animals with recoverable shuttle vectors with target genes makes possible the study of physiologically relevant parameters in exposure to environmental pollutants. Some of these factors include dose rate effects, tissue and organ specificity, age related effects, and diseased versus normal differences. These factors can be thoroughly examined in vivo since transgenic technologies provide the experimental system needed to evaluate them. The NIEHS is issuing this RFA in recognition of the potential of transgenic technologies in helping to elucidate the molecular mechanisms by which environmental agents cause disease. Research Goals Transgenic animals genetically designed animals created by the introduction of DNA coding for specific genes into the genome of pre implantation embryos are model systems that provide a tool to identify and characterize the expression of targeted genes. For example, this technology has facilitated the identification of chemically induced mutations and has helped in determining the mechanism of such mutations. It has helped to elucidate the mechanisms responsible for tissue specific and developmentally regulated gene expression, and has been instrumental in identifying signal transduction pathways and hormonal factors that modulate the activity of genes. However, with the exception of very few specific genes (e.g., AH receptor, methyl guanine methyl transferase, methallothioneins, and CYP1A1) the transgenic technologies have not been extensively utilized to investigate how environmental agents alter gene expression and cause disease. Therefore, this RFA is issued to encourage research that uses transgenic animal model systems to study molecular toxicology. It is anticipated that these investigations will allow innovative approaches in understanding the mechanism of gene alteration by environmentally relevant xenobiotic agents at the genome level, and the establishment of the nature of the xenobiotic induced gene expression in specific target cells and organs. Collaborative research efforts between investigators skilled in transgenic technologies and members of the environmental health research community, as well as scientists from closely related disciplines, are especially encouraged. Because the NIEHS has issued a Program Announcement, PA-90-22 "Development and Utilization of Transgenic Animal and Cell Models in Studies of Environmental Mutagenesis and Associated Health Effects," applications proposing the development and/or use of transgenic models to screen suspected cancer causing chemicals will be considered non-responsive to this RFA. The following areas 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 Research efforts may be directed at the creation of new transgenic animals with specific genes whose expression is altered by environmental agents, the induced responses are tissue and organ specific, and a relationship between toxicant exposure in target organs and subsequent development of disease sequelae may be established. For example, - new transgenic animals may be developed for the identification and characterization of genes that are involved in modulation of the cellular signaling pathways that lead to the xenobiotic induced health effects. - transgenic animals could be designed to improve our understanding of the correlation between chemical induction or suppression of programmed cell death or apoptosis and subsequent health consequences. o Transgenic animals could be used to study the over expression or inappropriate expression of xenobiotic inducible genes in order to understand the molecular basis of tissue specific and stage specific gene expression following exposure to the environmental agent. o New transgenic animals could also be used to study the regulation of DNA repair with emphasis on the identification and characterization of novel systems, and the molecular dissection of the genetic elements responsible for the cellular response. For example, studies may be designed to: - investigate cell and tissue specific expression of the DNA repair genes induced by xenobiotic agents, - study the interactions between the environmentally induced repair pathways, transcriptional induction, cell cycle arrest, and DNA replication. Research studies directed toward potential implications of environmental agents in non cancer disease endpoints are strongly encouraged. Therefore, new transgenic models may be developed for the identification of environmental agents that cause non cancer health effects, including, but not limited to, neurological, reproductive/developmental, immunological or cardiovascular diseases. Studies proposing the development and/or use of transgenic animals for the screening of cancer causing agents are not appropriate for this RFA. LETTER OF INTENT Prospective applicants are asked to submit, by May 10, 1996, 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. It is important to consider during the planning phase of the application, that the requested direct costs for the R01 applications submitted in response to this RFA may not exceed $200,000 per year. 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 SPECIAL REQUIREMENTS Applicants should request funds for one trip per year to the NIEHS in Research Triangle Park, North Carolina for an annual meeting of grantees. 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 Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: girg@drgpo.drg.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 also 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 June 10, 1996. If an application is received after that date, the Division of Research Grants (DRG) may contact the applicant to determine whether it will be returned to the applicant or reviewed with unsolicited applications for the next regular receipt date. 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. In addition, 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. REVIEW CONSIDERATIONS Because the scope of the research proposed in response to this RFA encompasses the interest of several NIH institutes and centers, applications might receive dual assignments based on the established PHS referral guidelines. Applications will be administratively reviewed by NIH staff for completeness and responsiveness to this RFA. Applications found to be incomplete or non responsive to this RFA will be returned to the applicant without further consideration. Those 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. Those applications judged by the study section panel to be non competitive will be administratively withdrawn from competition. Those applications judged to be competitive, deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed at the study section meeting, assigned a priority score, and receive a second level review by the EHS national advisory council. Review Criteria The following criteria will be considered: o scientific, technical, or medical significance and originality of the proposed research as it relates to the utilization of transgenic models to increase our knowledge of health effects of environmental toxicants; 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, particularly in the area of transgenic technologies; 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 1996. 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: Jose M. 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) 541-4500 FAX: (919) 541-2843 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) 541-7628 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No.93.113, 93.114 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, 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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