ENVIRONMENTALLY INDUCED CARDIOVASCULAR MALFORMATIONS RELEASE DATE: April 3, 2002 PA NUMBER: PA-02-093 (see NOT-ES-04-004) EXPIRATION DATE: June 1, 2004, unless reissued National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The National Institute of Environmental Health Sciences (NIEHS) invites applications to study environmental agents that cause cardiovascular malformations (CVMs). The purposes of this Program Announcement (PA) are to stimulate research to characterize environmental agents that cause alterations in the development of the cardiovascular system and thereby lead to cardiovascular malformations, and to investigate the cellular and molecular mechanisms involved in the development of these malformations. The use of mammalian and non-mammalian animal models, including transgenic and gene knock-out animal models, and of state-of-the-art molecular biology techniques such as genomics and proteomics is encouraged, as well as collaborations between environmental health scientists and developmental biologists, to develop research programs to address the high rate of cardiovascular malformations. RESEARCH OBJECTIVES Background Cardiovascular malformations (CVMs) are the most common type of birth defect among live births in the US, occurring in approximately 0.8 percent of live births. The most common types of CVMs include atrial or ventricular septal defects, transposition of the great vessels, persistent truncus arteriosus, teratology of Fallot, and coarctations. Despite the importance of these in malformations, both in terms of human suffering and cost to the healthcare system, the causes of most cases of CVMs are not known. Etiologic factors that have been identified include genetics, maternal diseases, such as diabetes, certain drugs, such as phenytoin and cocaine, and dietary factors, such as folic acid deficiency, vitamin A excess, and copper deficiency. In addition, certain environmental chemicals have been shown to be associated with cardiac malformations. For instance, in one large epidemiological study of cardiac malformations, the Baltimore-Washington Infant Study, exposure to such environmental factors as paints, solvents and degreasers, and pesticides, were associated with increased cardiac malformations. Epidemiological studies have also reported CVM associations with air pollutants (ozone and carbon monoxide) and trichloroethylene (TCE). In addition, environmental contaminants such as TCE, bis-diamine, and dioxin have been shown to be cardiac teratogens in animal studies. Despite the evidence for an environmental role in CVMs, the list of environmental agents tested for teratogenic effects on the heart is limited and relatively little research has been done on the cellular and molecular basis of the teratogenic effects of environmental agents or on the possible interactions between environmental exposures and other factors such diet and genetics. Recent advances in genomic and molecular biology technology and in the understanding of the development of the fetal heart, make this an opportune time to initiate such studies. General considerations: o Chemicals to be studied can represent known teratogens, such as trichloroethylene, or suspected teratogens, such as components of air pollution. Studies of mixtures are also acceptable. o In characterizing the actions of known or potential cardioteratogens, dose-response curves should be determined, and the dose ranges should include environmentally relevant doses. o The use of state-of-the-art technologies, such as genomic and proteomic technologies, is encouraged. o Studies to determine interactions between environmental exposures and genetics and/or nutritional factors are highly encouraged. o The use of genetically altered model organisms, such as transgenic animals and non-mammalian species, is encouraged. o Proposals should take into consideration the metabolism of environmental chemicals and the proximal metabolite to which the fetus is exposed. o In general in vivo and organ cultures procedures should be used, except in studies in which the ultimate CVM is known and in vitro experiments are proposed to examine responses of specific fetal cell types, to determine cellular and/or molecular mechanisms. Specific areas of interest to NIEHS include, but are not limited to the following: o Characterization of new potential environmental cardioteratogens. This characterization would include the types of CVMs induced, dose-response evaluation, identification of specific windows of vulnerability to the agent, and development of preliminary data for further mechanistic studies. o Use of forward and reverse mutagenesis studies in model organisms to determine the genes altered by specific cardiovascular developmental toxicants and the relationship of the altered gene activity to dysmorphogenesis. o Characterization of global gene expression profiles in the developing heart of model organisms associated with the normal range of development and after a developmentally toxic exposure. The relationship between the changes in gene expression and the developmental lesion should be assessed. o Use of genomic and/or proteomic profiling to determine how well data on toxicant-induced malformations can be extrapolated across species. o Identification and evaluation of specific signal transduction pathways and the associated genetic regulatory circuits that might be sites of action of developmental cardiovascular toxicants. The causal relationships between exposure and the CVMs should be developed. o Determination of the potential for interactions between exposures to environmental agents and genetic susceptibility that increase the risk for cardiovascular developmental toxicity. Special Requirements o This initiative focuses on mechanisms of development of CVMs. Therefore, proposals dealing with human epidemiological or clinical studies will not be considered as responsive. In some cases, use of human tissues in mechanistic studies could be considered responsive. o Proposals solely designed to screen a large number of agents will not be considered responsive. Screening of members of specific classes of agents is responsive as long as follow-up mechanistic studies of these agents are included. o Proposals should focus only on malformations of the heart and major vessels, e.g., the aorta, vena cavae, pulmonary artery, and pulmonary vein. o For this PA, diet will not be considered an environmental agent, and can only be considered in the context of interactions with environmental agents MECHANISM(S) OF SUPPORT This PA will use the NIH R21 and R01 award mechanism(s). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The total project period of an R21 proposal may not exceed two years, and the total direct costs, including third party facilities and administrative costs, may not exceed $100,000 per year. The objective of the Exploratory/Developmental Grant (R21) mechanism is to encourage applications for one-time grants to support 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 new technologies, techniques, or methods, or initial research and development of data upon which significant future research may be built. Applications will be considered as high impact if they demonstrate the potential for ground-breaking, precedent-setting significance, and high risk because they either lack sufficient preliminary data to ensure their feasibility, or involve using a new model system or technique. While this PA is intended to encourage innovation and high impact research, and while minimal preliminary data are expected to be described in the application, applications should clearly indicate that the proposed research and/or development is scientifically sound, that the qualifications of the investigators are appropriate, and that resources available to the investigators are adequate. As the R21 grant project cannot be renewed, if sufficient data are generated during the term of the award, investigators could then apply for further funding through regular research grant, e.g., the research project grant (R01) mechanism. On the other hand, R01 grant applications should be grounded in more established model systems and methodologies with which the investigators have experience, as evidenced by preliminary data in the application and/or publications in peer-reviewed literature, while at the same time being innovative and moving the field forward. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (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 format. Otherwise follow the standard instructions for grant 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 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 questions about scientific/research issues 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-23 111 T.W. Alexander Drive (for express/courier service) Research Triangle Park, NC 27709 Telephone: 919-541-3289 FAX: 919-541-5064 Email: mastin@niehs.nih.gov o Direct your questions about financial or grants management matters to: Ms. Carolyn Mason Grants Management Official Grants Management Branch Office of Program Operations Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, EC-22 111 T.W. Alexander Drive, (for express/courier service) Research Triangle Park, NC 27709 Telephone: (919) 541-1373 FAX: (919) 541-2860 Email: mason6@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 http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov APPLICATION RECEIPT DATES Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. 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 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 SPECIFIC INSTRUCTIONS FOR APPLICATIONS THAT REQUEST $500,000 OR MORE PER YEAR Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the NIEHS program staff at least six weeks before submitting the application, i.e., as you are developing plans for the study, 2) Obtain agreement from the NIEHS staff that the NIEHS will accept your application for consideration for award, and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 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 20817 (for express/courier service) APPLICATION PROCESSING Applications must be received by or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm 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 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 Receive a written critique. 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 second level review by the appropriate national advisory council or board. REVIEW CRITERIA Note that the page limit for the Research Plan in R21 applications under this Program Announcement is 15 pages, as opposed to 25 pages for R01 applications. 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 performances are not applicable for this mechanism. ADDITIONAL REVIEW CRITERIA In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below.) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. 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 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 AMENDMENT "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. This policy applies to all initial (type 1) applications submitted for receipt dates after October 1, 1998. 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://grants.nih.gov/grants/stem_cells.htm and 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 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. 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 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 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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