PAR-04-104: THE FETAL BASIS OF ADULT DISEASE: ROLE OF THE ENVIRONMENT

Department of Health
and Human Services (HHS)

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THE FETAL BASIS OF ADULT DISEASE: ROLE OF THE ENVIRONMENT RELEASE DATE: May 14, 2004 PA NUMBER: PAR-04-104 EXPIRATION DATE: August 13, 2004, unless reissued. Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institute of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.113, 93.114 LETTER OF INTENT RECEIPT DATE: July 10, 2004 APPLICATION RECEIPT DATE: August 12, 2004 THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions 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 Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THE PA This PA replaces PAR-03-121. 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. It is now clear that in many cases the fetus is more sensitive than the adult to the same environmental insults. Exposure to environmental agents during early 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 and on functional alterations whose effects are readily observable early in development. 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 effects of in utero exposures that cause permanent functional changes that are not overtly, grossly teratogenic yet that result in increased susceptibility to disease/dysfunction later in the life span. This program announcement seeks to encourage the application of the new high-throughput functional-genomic, metabonomic, proteomic, and bioinformatic technologies to pursue an understanding of these latent effects of in utero environmental insult. 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. Most of the supporting studies in this area have concentrated on grossly altered nutrition in utero and its striking influence on multiple aspects of adult health and disease risk. 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. In support of the Barker hypothesis, epidemiology studies have shown that markers of malnutrition, such as 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. In addition to malnutrition, environmental exposures present during in utero development can have profound influences on fetal growth. 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 interaction 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. Another promising area for investigation is how environmental prenatal exposures might alter immune system programming. The development of the immune system, including the development of the repertoire of reactive lymphocytes that will exist in postnatal life, begins prenatally. Alterations of the fetal immune environment might pre-program the highly sensitive fetal immune system for aberrant immune regulation, leading to a loss of tolerance to self-antigens and resulting in an increased risk for autoimmune disease. These changes might manifest in adult life and perhaps only after a second exposure to related environmental chemicals. There is evidence, for instance, that mice exposed prenatally to estrogenic compounds appear to develop normal immune systems. However, when stimulated with certain environmental chemicals, they can show an increased susceptibility to autoimmune disease. Similarly, there is evidence in humans and experimental animals that prenatal exposure to immunosuppressive drugs can lead to immune alterations in the mature animals, including development of autoantibodies and a higher risk of autoimmune disease in susceptible animals. Obesity is a disease whose prevalence has risen dramatically in developed countries over the past two-to-three decades reaching epidemic proportions in the United States. It is mainly considered to be caused by overeating and lack of physical activity on a background of genetic predisposition. The major environmental influence on obesity thus has been in utero and postnatal nutrition. A large number of epidemiological studies have demonstrated a direct relationship between birth weight and body mass index attained later in life. Indeed the data support the seeming paradox of increased adult adiposity associated with both ends of the birth weight spectrum: higher body mass index with higher birth weight and increased central adiposity with lower birth weight. Recent data support the hypothesis that nutrition is not the only environmental influence that may have an effect on obesity. There is increasing evidence that in utero exposure to environmental chemicals at environmentally relevant concentrations may alter developmental programming of adipose tissue and/or gastrointestinal-hypothalamic centers via irreversible alterations in tissue specific function as a result of altered gene expression. The chemicals that appear to be the most likely candidates for altering in utero tissue function that may result in obesity later in life include environmental estrogens such as diethylstilbestrol and bisphenol A, as well as other estrogenic endocrine disruptors, such as dioxin and nicotine. More data are needed to show proof-of-principle, not only with these chemicals. In addition, the field needs to be expanded to determine which chemicals and chemical types could have an impact on adolescent and adult obesity via in utero exposure. 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 might 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 Note that this PA expands the areas of interest described in the previous FeBAD PAs (PAR-02-105 and PAR-03-121). In addition to the adult onset disorders/dysfunctions noted in the two previous FeBAD PAs, the study of diseases and dysfunctions of adolescence, including abnormal onset of puberty, will now be considered responsive. o To provide a sound mechanistic understanding of fetal programming of adult disease, studies supported by this initiative must involve whole animal developmental exposures during gestation. Applicants can propose studies using transgenics, model organisms, or rodent models. For the purpose of this initiative, human studies (clinical or epidemiology) are not responsive. o Applicants must study an environmental agent/chemical/stressor to which there is human exposure and the potential for in utero exposure. This can include any endocrine active chemical(s) or organic solvents, particulate matter (PM), pesticides, nutritional supplements, phytochemicals or metals. Nutrition alone cannot be used as an in utero exposure but can be studied in conjunction with another exposure. o Applications must propose studies that focus on in utero exposures, but additional exposures at other time points (e.g., exposure beginning in utero and extending to postnatal period; exposure in utero followed by adult exposure) can be included. o This initiative encourages the use of the new technologies of gene expression profiling, and where appropriate, the examination of epigenetics (methylation, imprinting, and chromatin remodeling) to understand the mechanism responsible for the increased susceptibility to disease as a result of in utero exposure. o Applications must link in utero exposures to changes that are tissue specific and irreversible, such as changes in gene expression or methylation or changes in cell numbers, locations, or interactions, that will affect tissue function but are not considered teratogenic. These changes will then need to be correlated with the diseases/dysfunction studied in the adult or adolescent animal. o A specific adult or adolescent onset disease or dysfunction must be the focus of the application with emphasis on the role of in utero exposure and tissue specific changes in function in the fetus to the adolescent/adult onset or severity of the disease. Applications that are not focused on a specific adolescent/adult disease or dysfunction are not responsive. For example, applications that focus on in utero exposures as triggers of diseases of childhood are not responsive to this specific announcement. o Applications must focus on one of the following five emphasis areas: the reproductive tract, the cardiopulmonary system, the brain/nervous system or the immune/autoimmune system and obesity. Diseases of tissues or organ systems other than the five described here are not responsive to this specific announcement. The diseases of special interest to NIEHS with respect to this initiative include reproductive/hormonal (fertility, endometriosis, fibroids, premature menopause, polycystic ovary syndrome, prostate/ovary/breast cancer, or early or late onset of puberty) cardiopulmonary (heart disease, atherosclerosis, hypertension, chronic obstructive pulmonary disease, adult asthma) and brain/CNS neurodegenerative diseases Parkinson's, Alzheimer s, immune/autoimmune (altered immune responsiveness, systemic or tissue specific autoimmune diseases of adulthood) and adolescent or adult obesity and related problems of metabolic syndrome and diabetes. 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 five emphasis areas. o Applicants should be cognizant of the possible confounding effects of dietary components, especially phytoestrogens and other estrogenic components, when assessing all endpoints, but especially obesity. Consideration should be given to using synthetic diets and the chosen diet should be justified in relation to the possibility of confounding effects. o Critical areas of expertise that are required of applicants include developmental biology/toxicology and disease pathophysiology. Expertise in technologies such as gene expression profiling and proteomics (including data analysis and interpretation of global gene expression), epigenetics alterations, cell signaling, and signal transduction are strongly encouraged. MECHANISM(S) OF SUPPORT This PA will use the NIH exploratory/developmental (R21) award mechanism. As an applicant, you will be solely responsible for planning, directing and executing the proposed project. 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; and 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 data to ensure their feasibility, or involve the use of a new model system or technique. This PA uses just-in-time concepts. It also uses the modular budgeting format. (see http://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 budget format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. FUNDS AVAILABLE It is anticipated that approximately $2 million in FY 2005 will be available to fund grants in response to this PA. An applicant for an R21 grant may request a project period of up to three years and a budget for total direct costs, not including third party facilities and administrative costs, not to exceed $100,000 per year. Applicants should include funds for a grantee meeting at NIEHS for each year of the award. 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 PA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. 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 institutions/organizations 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 PA 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 general questions or questions about scientific/research issues related to the cardiopulmonary or immune/autoimmune areas to: J. Patrick Mastin, Ph.D. Scientific Program Administrator Chief, Cellular, Organ and Systems Pathobiology 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 o Direct your questions about scientific/research issues related to the reproductive/puberty/obesity areas to: Jerry Heindel, Ph.D. Scientific Program Administrator Cellular, Organ and Systems Pathobiology 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 neurodegenerative area to: Cindy Lawler, Ph.D. Scientific Program Administrator Cellular, Organ and Systems Pathobiology 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: 919-316-4671 Fax: 919-541-5064 Email: lawler@niehs.nih.gov or Annette Kirshner, Ph.D. Scientific Program Administrator Cellular, Organ and Systems Pathobiology 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: 919-541-0488 Fax: 919-541-5064 Email: kirshner@niehs.nih.gov o Direct your questions about financial or grants management matters to: Mr. Dwight Dolby Grants Management Specialist Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 (EC-22), 111 T.W. Alexander Drive Research Triangle Park, NC 27709 Telephone: 919-541-7824 Fax: 919-541-2860 Email: dolby@niehs.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: J. Patrick Mastin, Ph.D. Scientific Program Administrator Chief, Cellular, Organ and Systems Pathobiology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 (EC-23), 111 T.W. Alexander Drive Research Triangle Park, NC 27709 Telephone: 919 541-3289 Fax: 919-541-5064 Email: mastin@niehs.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at http://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. The title and number of this program announcement must be typed on line 2 of the face page of the application form and the YES box must be checked. Applicants should note that R21 applications have a page limitation of 15 pages for the Research Plan. APPLICATION RECEIPT DATE: Applications submitted in response to this program announcement will be accepted on August 12, 2004. SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget grant format. The modular budget 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 http://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 http://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 five 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) APPLICATION PROCESSING: Applications must be received by the receipt date of August 12, 2004. 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 unfunded version of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Undergo a selection 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 o Receive a written critique o Receive a second level review by the National Advisory Environmental Health Sciences 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The 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, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the 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. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: July 10, 2004 Application Receipt Date: August 12, 2004 Peer Review Date: November 2004 Council Review: February 2005 Earliest Anticipated Start Date: April 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 HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 http://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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm 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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