PROGRAM ANNOUNCEMENT (PA) TITLE: THE FETAL BASIS OF ADULT DISEASE: ROLE OF THE ENVIRONMENT PAR NUMBER: PAR-02-105 (see replacement PAR-03-121) RELEASE DATE: May 2, 2002 Letter of Intent Receipt Dates: July 10, 2002, 2003, 2004 Application Receipt Dates: August 12, 2002, 2003, 2004 This Program Announcement expires on August 13, 2004, unless reissued. PARTICIPATING INSTITUTES AND CENTERS (ICs) National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of this PA o Research Objectives o Mechanism of Support o Eligible Institutions o Funds Available o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA It is recognized that between two-percent and five-percent of all live-born infants have a major developmental defect. Approximately 40-percent of these defects are thought to be due to the effect(s) of an adverse exposure of a genetically pre-disposed fetus to intra-uterine environmental factors. Exposure to environmental agents during development can result in death, structural malformation, and/or functional alteration of the embryo/fetus. These toxicant-induced pathogenic responses are most likely the result of altered gene expression associated with altered cell production and cell differentiation involved in the establishment of cell lineages leading to the structural and functional character of the tissues, organs, and systems that arise from these lineages. The NIEHS has a significant program that addresses the role of developmental exposures on structural malformations i.e., classical birth defects. The new high-throughput functional-genomic, metabonomic, proteomic, and bioinformatic technologies now offer for the first time the opportunity to pursue an understanding of the role of in utero exposures to environmental agents in causing functional changes in organs and tissues that result in increased susceptibility to diseases later in life. The purpose of this program announcement with a set aside of funds and a Special Emphasis Panel review by the NIH Center for Scientific Review is to stimulate research in an important and emerging area of developmental toxicology: the effect of in utero exposures that cause permanent functional changes that are not overtly, grossly teratogenic and that result in increased susceptibility to disease/dysfunction later in the life span. It is becoming increasingly apparent that there is an environmental component to nearly every disease. In some cases the environmental trigger is an exposure experienced in the adult environment. However, it is now clear that in many cases the fetus is more sensitive to the same environmental insults and that the effect of exposures during development may have a far more detrimental effect on the etiopathology of the disease, both for the fetus as well as the adult later in life. RESEARCH OBJECTIVES The underlying scientific hypothesis behind the fetal basis of adult diseases has been developed by epidemiology studies and emphasized by Dr. David Barker in the United Kingdom. This hypothesis, named the Barker Hypothesis, proposed that prenatal origins of health and disease is one of the most important issues that affects our lives and that of our children. Dr. Barker has shown that during development fetuses respond to severe malnutrition by favoring the metabolic demands of the growing brain/CNS and heart at the expense of other tissues. The growing brain/CNS and heart tissue may not, however, escape entirely unscathed. The long-term consequences of this response are that the fetus is protected from death, is live-born, but is more prone to diseases later in life. The Barker Hypothesis studies concentrated on grossly altered nutrition as the source of the stress during development. These studies showed via epidemiology studies that low birth weight, small for gestation age, frank intra-uterine growth retardation (IUGR) or clinically abnormal thinness at birth strongly predicts the subsequent occurrence of hypertension, hyperlipidemia, insulin resistance, type 2 diabetes, ischemic heart disease, breast cancer or prostate cancer in adult life. Fetuses that are clinically malnourished during the first trimester of development are three times more likely to be obese as adults. Evidence has been presented in human populations that gross, heavy exposure to PM10 air pollution containing carcinogenic PAHs can be correlated with increased IUGR with a peak impact in the earlier portion of the first trimester - a most vulnerable period of the cell lineage expansion, differentiation, and cell interactions events of organogenesis and first growth. The concept of fetal programming of structural-functional formations during development has been proposed to explain these findings and the resultant research area is referred to as Fetal Basis of Adult Disease (FeBAD) research. Programming is the term used to describe lifelong changes in function that follow a particular event in an earlier period of the life span. While epidemiology studies have identified the phenomenon of metabolic programming, little is known about the mechanism(s) by which fetal insults lead to altered programming and to disease later in life. In addition, emphasis thus far has been on alterations in nutrition during development with virtually no focus on the role that exposures to environmental agents, such as air or water pollution, either alone or in combination with qualitative alterations in macro- or micro-nutrition (i.e. soy protein, phytoestrogens, isoflavones or other chemicals in herbal supplements or dietary sources), might have on this phenomenon. There is, however, evidence that some environmental agents, especially those with endocrine agonist or antagonist activity, may alter developmental programming via alteration in gene expression or gene imprinting that do not result in malformations but in functional deficits that do not become apparent until later in life. In the reproductive tract, the classic example of this phenomenon in the environmental area is the diethylstilbestrol (DES) story. In humans, in utero exposure to DES leads to an increase in vaginal adenocarcinoma around the time of puberty. In mice, neonatal DES exposure leads to an increase in uterine adenocarcinoma in adulthood. While the direct connection has not been made between in utero programming changes due to DES and later life disease, it is known that DES (in the animal studies) results in altered gene expression in the uterus that is irreversible without any noticeable gross alterations in uterine morphology. Other examples in the reproductive area include developmental exposures of the monkey to androgens that lead to polycystic ovary syndrome-like effects in the adult, data (still considered controversial) showing that environmental estrogens, such as DES, methoxychlor and bisphenol A, cause alterations in gene expression in the rat prostate that are irreversible and are correlated with increased prostate cancer, and data showing a link between in utero exposure to dioxin and endometriosis later in life in primates and rodents. Cardiopulmonary diseases in postnatal life have also been linked to prenatal exposure. The most well known example is the association between low birth weight (which is associated with poor maternal nutrition and perhaps corticosteroid exposure) and cardiovascular disease (e.g., myocardial infarcts) and predictors of future cardiovascular disease, such as hypertension and atherosclerosis, and complex metabolic disease, such as diabetes. In addition, studies have shown that maternal smoking is associated with deficits in lung function and with asthma symptoms in the offspring. Data indicate that these associations are independent of smoking status after birth. Some forms of neurodegenerative disease may have their origins in in utero exposures. For example, there is preliminary evidence that a bacterial stimulus (endotoxin) can produce cytokines that impair the development of the mesencephalic dopaminergic systems during pregnancy. This attenuation of the dopamine neurons during fetal development leaves the offspring with fewer dopaminergic neurons at birth and at possible increased risk for Parkinson's disease in later life. In a similar vein, there is preliminary evidence that exposure to environmental neurotoxins during dopaminergic development enhances the susceptibility to accelerated dopaminergic cell death during aging via the common molecular mechanism(s) of the alteration of stress-activated signal transduction pathways, expression of differentiation transcription factors, survival factors or phenotype marker proteins in the nigral dopaminergic neurons. Similarly there is evidence that in utero exposure to polycyclic biphenols (PCBs) leads to altered thyroid function and subsequent learning disabilities later in life. In all instances data are needed to show that the in utero exposures actually lead to an altered programming at the molecular level and that the disease/dysfunction is a direct result, albeit, temporally discordant in its onset and/or progression, of that altered programming. Based on the epidemiology data that support the Barker Hypothesis and the preliminary data showing alterations in gene expression and imprinting due to in utero exposures to some environmental agents, we propose that exposure to certain environmental chemicals as well as altered nutrition, or in combination with altered nutrition, will in some situations, not lead to easily identifiable structural malformations, but instead to alterations in developmental programming expressed as a permanently altered gland, organ or system potential. These states of altered potential would be a result of changes in gene expression, due to altered imprinting, and the underlining methylation-related protein-DNA relationships associated with chromatin remodeling. These effects may occur in a time specific (i.e. vulnerable window) and tissue specific manner and such alterations may be irreversible. The end-result is an animal that is sensitized such that it will be more susceptible to diseases later in life. The environmental insult could act via a one hit or two/three hit scenario. That is, there could be an in utero exposure that would lead by itself to pathophysiology later in life or there could be in utero exposure combined with a neonatal exposure (same or different compound(s) or adult exposure that would trigger the pathophysiology. The pathophysiology or functional change that results from the exposures/insult could lead to: a) the occurrence of a disease that otherwise would not have happened, b) an increase in risk for a disease that would normally be of lower prevalence, or c) either an earlier onset of a disease that would normally have occurred or an exacerbation of the disease. Finally, the pathophysiology could have a variable latent period from onset in the neonatal period, to early childhood, to pubertal, to early adulthood to late adulthood depending on the toxicant, time of exposure and tissue/organ affected and potentially transgenerational effects. Research Approaches Relevant to this PA The very nature of the problem mandates that the studies related to this initiative, at some time, involve whole animal developmental exposures with analysis of the fetus, embryo and pups, and well as later life disease/dysfunction incidence. These analyses can be done using transgenics, model organisms, or rodent models. Research proposed under this initiative must use environmentally relevant doses, dose response curves and the examination of the relationship between the molecular mechanism proposed and the disease/dysfunction studied. Human studies (clinical or epidemiology) are not responsive. However, it would be acceptable to propose studies to examine gene expression using human cells/tissues and as a prelude to future epidemiology studies. This initiative also requires the use of the new technologies of gene expression profiling, and epigenetics (methylation, imprinting and chromatin remodeling). The use of these technologies allows assessment of in utero exposure to environmental agents. A critical component of applications to this Program Announcement is the development of a direct correlation and eventually a cause and effect relationship between the alterations in gene expression during development (either increased, decreased or inappropriate timing) to alterations in signal transduction pathways and alterations in growth factors and cytokines and hormones that lead to a specific disease or dysfunction that occurs later in life. Another critical part of this initiative is the collaboration of developmental biologists/toxicologists with scientists studying the onset and exacerbation of adult onset diseases. All applications must show expertise in both developmental biology/toxicology and disease pathophysiology. In addition, a specific disease must be the focus of the application with emphasis on the role of in utero exposure and changes in gene expression in the fetus to the onset or severity of the disease. This initiative will focus on only the three areas that have the most preliminary data and, thus, show the most promise of success: the reproductive tract, the pulmonocardiovascular system, and the brain/nervous system. The diseases of interest to NIEHS with respect to this initiative include reproductive/hormonal (fertility, endometriosis, fibroids, premature menopause, polycyclic ovary syndrome, prostate/ovary/breast cancer) cardiopulmonary (heart disease, atherosclerosis, hypertension, chronic obstructive pulmonary disease, adult asthma) and brain/CNS (neurodegenerative diseases - Parkinson's, Alzheimer). It may be possible to submit applications to this initiative with an emphasis on other diseases as long as they are related to one or more of the above noted emphasis areas. It should be noted that these are all adult onset diseases. Thus this initiative has a focus on diseases that have a long latency. Diseases of childhood or puberty or diseases of other tissues and organ systems are not responsive to this specific announcement. Applicants to this program must link in utero and/or neonatal exposures during critical windows of development to changes in gene expression that are tissue specific (reproductive, cardiopulmonary and brain) and irreversible. These changes in gene expression will then need to be measured in the adult and correlated with the diseases/dysfunction studied with or without additional adult exposures. Applicants may study any environmental agent/chemical/stressor to which there is human exposure and the potential for in utero exposure. This includes any endocrine active chemicals and in addition, organic solvents, particulate matter, pesticides, nutritional supplements, phytochemicals and metals. Nutrition alone cannot be used as an in utero exposure alone but can be studied in conjunction with another exposure. Exposure to the environmental agent must be in utero but may also be neonatal and/or adult. MECHANISM OF SUPPORT This PAR will use the NIH exploratory/developmental (R21) award mechanism. The R21 grant award mechanism supports innovative, high-risk/high-impact research requiring preliminary testing or development; exploration of the use of approaches and concepts new to a particular substantive area; research and development of data upon which significant future research may be built. Applications will be considered high-impact if they demonstrate the potential for groundbreaking, precedent setting significance, and high-risk because they either lack sufficient preliminary date to ensure their feasibility, or involve the use of a new model system or technique. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This PAR uses just-in-time concepts. It also uses the modular budgeting format. (see https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign FUNDS AVAILABLE The NIEHS intends to commit approximately $2 million in FY 2003, 2004 and 2005 to fund new grants in response to this PAR. An applicant for an R21 grant may request a project period of up to three years and a budget for total direct costs, including third party facilities and administrative costs, not to exceed $100,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIEHS provide support for this program, awards pursuant to this PAR are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PAR and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research, and financial or grants management issues: o Direct your questions about scientific/research issues related to the reproductive/endocrine area to: Jerry Heindel, Ph.D. Scientific Program Administrator Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 (EC-23) Research Triangle Park, NC 27709 Telephone: 919-541-0781 FAX: 919-541-5064 Email: heindelj@niehs.nih.gov o Direct your questions about scientific/research issues related to the cardiopulmonary area to: J. Patrick Mastin, Ph.D. Scientific Program Administrator Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 (EC-23) Research Triangle Park, NC 27709 Telephone: 919-541-3289 FAX: 919-541-5064 Email: mastin@niehs.nih.gov Direct your questions about scientific/research issues related to the neurodegenerative area to: Annette Kirshner, Ph.D. Scientific Program Administrator Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 (EC-23) Research Triangle Park, NC 27709 Telephone: 919 541-0484 FAX: 919-541-5064 Email: kirshner@niehs.nih.gov o Direct your questions about financial or grants management matters to: Ms. Lerlita Garcia Grants Management Specialist Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 (EC-22) Research Triangle Park, NC 27709 Telephone: 919-316-4638 FAX: 919-541-2860 Email: garcia@niehs.nih.gov Although not participating in this PA, the National Institute on Drug Abuse (NIDA) is interested in funding research aimed at understanding the physiological and neurobiological consequences of in utero exposure to drugs of abuse, including inhalants (e.g. Toluene) that may be abused by pregnant women. NIDA is also interested in understanding the neurobiological consequences of in utero exposure of environmental chemicals that may confer risk or vulnerability to substance abuse disorder later in life. For more information on NIDA's pre-clinical in utero exposure program, please contact Dr. Pushpa Thadani at 301-443-6300, email: pt24e@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this PA 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 sent by the date listed at the beginning of this document. The letter of intent should be sent to: Ethel Jackson D.D.S. Chief, Scientific Review Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, EC-30 (79 T.W. Alexander Drive, 4401 Bldg, 3rd Floor) express mail Research Triangle Park, NC 27709 Telephone: 919-541-7846 FAX: 919-541-2503 Email: jackson4@niehs.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. Applicants should note that R21 applications have a page limitation of 15 pages for the Research Plan. APPLICATION RECEIPT DATES Applications submitted in response to this PA will be accepted on August 12, of 2002, 2003 and 2004. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. SENDING AN APPLICATION TO THE NIH Submit a signed, typewritten original of the application, including the Checklist, and four 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, one additional copy of the application must be sent to: Ethel Jackson D.D.S. Chief, Scientific Review Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 (EC-30) (79 T.W. Alexander Drive, 4401 Bldg, 3rd floor) express mail Research Triangle Park, NC 27709 Telephone: 919-541-7846 FAX: 919-541-2503 Email: jackson4@niehs.nih.gov APPLICATION PROCESSING Applications must be received by or mailed before the receipt dates described above. The CSR will not accept any application in response to this PA 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 a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIEHS. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the PA will be evaluated for scientific and technical merit by an appropriate peer-review Special Emphasis Panel convened by the CSR in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique. o 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. o Receive a second level review by the NIEHS National Advisory Council. 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? For R21 applications, the above stated criteria will be reviewed but it will be noted that the R21 is a developmental/exploratory grant mechanism that is used for high risk/high impact projects to generate preliminary data to develop novel hypotheses. Therefore, review standards for preliminary data and past performance are not applicable for this mechanism. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: July 10, 2002, 2003, 2004 Application Receipt Date: August 12, 2002, 2003, 2004 Peer Review Date: November 2002, 2003, 2004 Council Review: February 2003, 2004, 2005 Earliest Anticipated Start Date: April 2003, 2004, 2005 AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review. o Availability of funds. o Relevance to program priorities. REQUIRED FEDERAL CITATIONS PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.3113 and 93.114, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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