PEROXISOME PROLIFERATORS AND MECHANISMS OF CARCINOGENESIS Release Date: February 23, 1998 RFA: ES-98-003 P.T National Institute of Environmental Health Sciences Letter of Intent Receipt Date: April 1, 1998 Application Receipt Date: May 20, 1998 PURPOSE Environmental health research carried out by the National Institute of Environmental Health Sciences (NIEHS) provides a solid scientific foundation for understanding interrelationships between the environment, genetics and temporal factors as they relate to human disease and dysfunction. The NIEHS Division of Extramural Research and Training is responsible for developing and directing the investigator-initiated hypothesis-driven mechanistically-based research related to the NIEHS mission. Research conducted by the National Toxicology Program (NTP), centered at the NIEHS, focuses on the evaluation of environmental/industrial agents for their toxic effects using a broad array of assays and test systems and generates data to strengthen the scientific foundations for risk assessment. The goal of this Request for Applications (RFA) is to provide scientifically- based data to aid the NIEHS in understanding the mechanisms of action of agents under study by the NTP to further improve the risk assessment process, and, thereby, better protect the public health. This program, as outlined in this RFA, utilizes the R03 Small Grants Program to encourage investigator-initiated applications that will utilize frozen tissues from an NTP study involving exposure to peroxisome proliferators. It is anticipated that these investigator-initiated research projects will complement the NTP study by providing additional information on the mechanism(s) of action of the agents tested. 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, Peroxisome Proliferators and Mechanisms of Carcinogenesis, 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) 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. Foreign institutions and organizations are not eligible. 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 essentially 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 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 a maximum of $50,000 (direct cost) for a maximum of one year. Small grants are not renewable but may be extended for an additional year with no additional funds at the discretion of the applicant organization. FUNDS AVAILABLE The total estimated funds available for this small grants program is $400,000, which will support approximately four to six 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/NTP, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Peroxisome proliferators (PPs) represent a diverse group of chemicals with a high likelihood of clinical, occupational and environmental exposure to humans. A human heath concern exists because of the association between peroxisome proliferation and cancer in laboratory rodents. Chemicals considered as PPs include fibrate hypolipidemic drugs, phthalate ester plasticizers, herbicides such as 2,4-D and endogenous, long chain fatty acids. Characteristic responses of rodent hepatocytes to PPs include hepatomegaly, a marked proliferation of peroxisomes in parenchymal cells, and an increase in peroxisomal -oxidation of fatty acids. These responses are thought to be mediated by the PP activation of a steroid hormone-like receptor termed the peroxisome proliferator-activated receptor (PPAR). PPARs are ligand-activated transcription factors that control gene expression by interacting with specific DNA response elements located upstream of responsive genes. Despite being regulated by PPAR, the effects of PPs on the induction of responsive genes varies widely depending on the PP itself as well as the species of test animal. Hepatocarcinogenicity has been produced in rats and mice by the protypic peroxisome proliferator WY-14,643 and gemfibrozil and has been reported for di-(2-ethylhexyl)phthalate. Hepatocellular carcinomas have been produced in rats administered clofibrate. This class of chemicals including di(2-ethylhexyl)phthalate and gemfibrozil have been shown not to be mutagenic. Consequently, the mechanism of carcinogenicity is unclear, although biochemical and physiological effects associated with hepatic peroxisome proliferation have been implicated in the etiology of liver toxicity and carcinogenicity. Understanding the mechanism(s) of peroxisome proliferator- induced carcinogenicity in rodents will allow evaluation and comparison to possible mechanisms in humans. Research Goals To define the mechanism(s) whereby peroxisome proliferators induce cancer in rodents the NTP designed and carried out 14-28- and 90-day studies with dibutyl phthalate, WY-14,643, gemfibrozil and 2,4-(Dichlorophenoxy) acetic acid (2,4-D) in male rats, mice and hamsters. Numerous endpoints were measured in order to identify gene products activated by PPs that are mechanistically linked to the carcinogenicity of this class of compounds in rodents. It is anticipated that these would serve as biomarkers to ascertain if similar gene products were produced in humans exposed to PPs thus indicating exposure presented a risk of cancer in humans. A detailed toxicity study design including species studied, doses tested, endpoints measured and tissues available for investigator-initiated studies under this RFA may be obtained from the NIEHS home page at the following address: http://www.niehs.nih.gov/dert/ppar.htm To aid the NTP in developing the scientific data set necessary to define the mechanism of tumor development by these agents, the NTP, in coordination with the Division of Extramural Research and Training, proposes to add additional investigator-initiated studies from this RFA to these studies. Projects that will provide biochemical endpoints that are related to (or predict) liver carcinogenicity of peroxisome proliferators are requested. They include but are not limited to: o Cellular effects/biochemical changes in liver related to peroxisome proliferator-induced carcinogenicity (i.e., cell mitosis/apoptosis). o The relationship between DNA repair enzyme activity or oxidative DNA damage and peroxisome proliferator-induced carcinogenicity. o Oxidative stress, reactive oxygen species, antioxidant levels and peroxisome proliferator-induced carcinogenicity. o Characterization of protein changes with chemical, species, time and dose of peroxisome proliferation and carcinogenicity. o Gene expression and peroxisome proliferator-induced carcinogenicity. o Induction of cytochrome P450 isozymes or other oxidative stress associated enzymes. o PPAR distribution (5 subtypes) in relation to carcinogenicity. Research applications should be hypothesis driven, mechanistically-based and must be justified as to how this NTP study is unique in providing tissues needed for the studies proposed, how the studies can be accomplished within the budget and personnel proposed, and how the data will aid in understanding the mechanism of the carcinogenicity of peroxisome proliferators. Study Design Considerations o Applications must be directly related only to the liver carcinogenicity of the test chemicals, other endpoints such as reproductive or immune are not considered responsive to the RFA and will not be accepted. o Since the NTP study is already completed, investigator-initiated studies must be limited to utilization of the available specific frozen or formalin fixed tissues. o Tissues will be shared by these successful applicants of this RFA. Applicants should contact the NTP (see inquiries section) for tissue availability before finalizing their applications. o It is expected that all studies will use tissues from a rodent (mouse and/or rat) plus, hamster tissues in order to compare a responsive and nonresponsive species. Investigators must, in their applications, be specific and justify the tissues needed, preparation of tissues needed, doses needed, shipping requirements, animal species to be studied and dosing times to be studied. o Applicants need not propose to examine all studies or all time points or all dose levels. Investigators should carefully examine the NTP study design and design a proposal to specifically address a particular question using the appropriate number of tissues, chemicals and necropsy times. Applicants are requested to set aside funds for a trip to NIEHS to discuss their results and to be prepared to integrate their findings into an NTP final report. Inclusion of data in the NTP final report would not preclude independent publication. The investigator-initiated work may be published independently at the discretion of the investigators. Investigators may also have access to NTP data on, for example, blood, tissue, adipose tissue levels of chemicals which may be needed for analysis and interpretation of their own data derived from this collaborative study. LETTER OF INTENT Prospective applicants are asked to submit, by April 1, 1998, 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, 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, MD EC-24 111 T.W. Alexander Drive 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. These forms 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 301/710-0267, Email: ASKNIH@od.nih.gov. THE FOLLOWING ARE SUPPLEMENTAL INSTRUCTIONS: o The application must detail the specific budget categories and percent efforts that will be required. This will be a $50,000 maximum award - direct cost. The budget must be justified. Equipment will be limited to $5,000. o The applicant must be explicit in describing the proposed interface between the NTP study design and the proposed project. o Preliminary data are not required except to indicate the expertise of the Principal Investigator to carry out the proposed studies. o The Research Plan (Specific Aims, Background and Significance, Preliminary Studies, Research Design and Methods sections) is not to exceed Ten (10) pages. Tables and figures are included in the Ten-page limitation. Applications that exceed page limitations or PHS 398 requirements for font size (height or letters), type density (characters per inch), and margins (see PHS 398 directions) will be returned to the investigator. o Do not use the appendix to circumvent the page limitation. The RFA Label available in the PHS 398 (rev. 5/95) 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: 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 Dr. Ethel Jackson at the address listed under LETTER OF INTENT. 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 May 20, 1998. 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 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 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 review, comments on the following aspects of the application will be made 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 the assignment of the overall score. (1) Significance: If the study is completed, how will scientific knowledge on the mechanism of peroxisome proliferator-induced hepatocarcinogenesis be advanced? (2) Approach: Are the designs, methods and analysis adequately developed and appropriate to the aims of the project? Does the applicant acknowledge potential problems and consider alternative tactics? Is there an explanation of how the data obtained will be integrated with the NTP data to provide a more comprehensive analysis of the mechanism of carcinogenicity of the test agents? Is the study focused on the relationship among exposure, endpoint, species and hepatocarcinogeneses? (3) Innovation: Is there justifications to how the tissues are unique to the proposed study and how the study will make the best of the tissues? (4) Investigator: Is the investigator appropriately trained and well suited to carry out the proposed project? Is the work proposed appropriate to the experience level of the principal investigators and other researchers, (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Is there evidence of institutional support? NOTE: If the project can be completed without the aid of this NTP study, the proposal will not qualify under this RFA. AWARD CRITERIA The anticipated date of award is September 1998 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 RFA. INQUIRIES Written, telephone or e-mail 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: Jerrold J. Heindel, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD EC-23 111 T.W. Alexander Drive Research Triangle Park, NC 27709-2233 Telephone: (919) 541-0781 FAX: (919) 541-5064 Email: heindelj@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, MD EC-22 111 T.W. Alexander Drive Research Triangle Park, NC 27709-2233 Telephone: (919) 541-7628 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov For clarification of NTP study design or for information on tissue availability contact: Michael L. Cunningham, Ph.D. DABT Environmental Toxicology Program National Institute of Environmental Health Sciences P.O. Box 12233 MD B3-10 111 T.W. Alexander Drive Research Triangle Park, NC 27709-2233 Telephone: (919) 541-3799 FAX: (919) 541-4632 Email: cunning1@-niehs.nih.gov 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, 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 Public Health Service (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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