Full Text HL-95-001 GENE-NUTRIENT INTERACTIONS IN THE PATHOGENESIS OF CONGENITAL HEART DEFECTS NIH GUIDE, Volume 23, Number 33, September 16, 1994 RFA: HL-95-001 P.T. Keywords: National Heart, Lung and Blood Institute Letter of Intent Receipt Date: December 16, 1994 Application Receipt Date: April 21, 1995 PURPOSE The Division of Heart and Vascular Diseases invites applications to conduct research into the relationship between genes and nutrients in the etiology and prevention of Congenital Cardiovascular Malformations (CCVM). One goal is to foster basic research into the effects of nutrients on embryologic and fetal development of the cardiovascular system. Approaches may include cell and organ culture, the generation of genetically altered animal models and the use of molecular biology and molecular genetics to elucidate the mechanisms underlying those effects. A second goal is to encourage small epidemiologic investigations into the role of nutrients in the pathogenesis of human CCVM. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Gene-Nutrient Interactions in the Pathogenesis of Congenital Heart Defects, is related to the priority areas of maternal and infant health, infant mortality and nutrition. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. Awards in connection with this RFA will be made to foreign institutions only for research of very unusual merit, need and promise and in accordance with PHS policy governing such awards. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research grant (R01). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to the present RFA may not exceed five years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Since a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. FUNDS AVAILABLE The total funds available for the first year of this program (direct plus indirect costs) are $2.00M. Funding is expected to begin in September 1995. It is anticipated that no more than eight grants will be awarded under this program. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plan of the NHLBI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Administrative adjustments in project period and/or amount of support may be required at the time of the award. In order to more evenly distribute administrative workload and reduce the number of awards with July 1 or September 30 start dates, the NHLBI will award ten months of time and money for the first competing budget period of this project. This action results in a project period of 58 months. Investigators should plan their research projects and budgets within these timeframes. RESEARCH OBJECTIVES Disciplines and Expertise Expertise appropriate for investigators includes but is not restricted to: developmental biology, human or animal genetics, molecular biology, epidemiology, experimental nutrition, human nutrition and dietetics, biochemistry, and biostatistics. Background Congenital cardiovascular malformations (CCVM) present our society with an enormous burden of grief and expense. About eight percent of all deaths during the first year of life are due to CCVM. Each year approximately 30,000 babies are born with CCVM, of whom 2,900 will die before their first birthday. Birth defects comprise the largest component of infant mortality in the United States and 42 percent of deaths due to birth defects are caused by CCVM. All U.S. population groups are afflicted by these relatively high rates. For example, although much of the 2.5 fold elevation in infant mortality of African American infants is due to prematurity and Respiratory Distress Syndrome, these infants experience excessive deaths from CCVM as well. Many of the children with CCVM who survive infancy go on to suffer sustained disease. After asthma and mental retardation, CCVM represent the most frequent cause of serious chronic childhood morbidity, being more common than cystic fibrosis and hemophilia. CCVM in older children and adolescents are accompanied by chronic use of medications, multiple medical procedures, hospitalizations, and often, repeated open heart operations requiring cardiopulmonary bypass. Not surprisingly, these children are likely to suffer impaired physical and social development. Furthermore, deaths due to CCVM occur throughout childhood, adolescence and young adulthood. Three thousand six hundred children under age 15 die annually from CCVM; 700 of these are more than 1 year old. In 1992, nearly $500 million was spent to cover the costs of 44,000 hospitalizations of children under age 15 with CCVM. The societal costs of serious CCVM are unknown, but are certainly very high, considering the loss of productive years of life, the burden on caregivers, and the magnitude of medical expenses. For many years the etiology of CCVM was thought to be multifactorial, involving a complex interaction of the feto-placento-maternal unit and teratogens. Genes were thought to play only a small role, in part because few children with CCVM lived long enough to reproduce; this hampered detection of the genetic nature of many of these defects. After a decade of focused research, much of which was funded by NHLBI, there are new insights into the pathogenesis of CCVM. It now appears that many if not most CCVM are caused by gene mutations. A genetic etiology is now either strongly suspected or confirmed for at least eight different structural cardiovascular malformations. One of these, supravalvular aortic stenosis, is now known to be caused by a mutation in the elastin gene. It is possible that the abnormal genotype causing as many as half of these eight CCVM may be identified relatively soon. Given the unsatisfactory nature of current treatments for many CCVM, it seems prudent to consider strategies for prevention. Other than genetic counseling and avoidance of pregnancy, there are no interventions available to reduce the frequency of offspring with congenital heart disease. Recent findings in the pathogenesis and prevention of neural tube defects, however, support the concept that risk of other birth defects, including CCVM, may in some cases be related to maternal nutrient intake. This concept is buttressed by the results of clinical trials that have focused on the role of folate in the prevention of neural tube defects. Approximately half of all NTD, whether among the general population or among high risk mothers who have already borne a child with an NTD, may be prevented by daily supplementation of the maternal diet with 4 mg of folate interaction between the genetic background of the mother or fetus and the increased need for folate or other nutrients but the relative importance of such interactions in the causation of most cases of NTD is unknown. Recent genetic research on NTD has associated the location of different NTDs (ranging from anencephaly to sacral meningocele) with a variety of specific maternal exposures such as hyperthermia or low folate intake. NTDs are, by definition, the result of failure of early morphogenetic processes. The mechanisms underlying neural tube closure have been studied in considerable detail. There appear to be five different "zippers" that span the length of the neural tube and function to close it during development. These zippers are presumably under the control of one or more genes, mutations in which would cause an NTD in the region of that zipper. Proper function of two of these zippers appears to be sensitive to folate deficiency. These preliminary findings in the pathogenesis of NTD support the concept that risk of other types of birth defects may also be affected by maternal nutrient intake. Progress being made in elucidating gene-nutrient interactions in organs other than heart lends credence to the possibility that such connections could be made for CCVM. For example, Vitamin C has been shown to be required growth, malformations mirroring part of the CRBP I expression pattern during development. CRABP I transcripts, on the other hand, are found in tissues which are separate and distinct from those expressing CRBP I. Saturation of the cytoplasmic pool of CRABP I with large doses of exogenous RA could be expected to cause homeobox or other genes to be turned on inappropriately. This may be part of the mechanism by which one metabolite of vitamin A, isotretoin, consumed in the first trimester of pregnancy, produces conotruncal malformations in the human embryo. Not all of the malformations that may be secondary to gene-nutrient interactions are necessarily the result of inadequate or excessive maternal nutrient intake. Rather, mutated genes may interact with normal nutrient intake to produce an abnormal phenotype. This concept is well illustrated by the Pallid (pa) mouse mutant. When fed a normal diet, mice homozygous for the pa allele produce offspring which are ataxic due to failure of otolith formation. When these same genotypically mutant mice are fed supraphysiologic supplements of the trace element manganese, their pups are phenotypically normal, showing no signs of ataxia. Moreover, genotypically normal rats fed a diet deficient in manganese produce offspring with the Pallid phenotype of ataxia and absent otolith formation. The manganese deficient phenotype has also been reported in chick, mouse and guinea pig and appears to result from depressed mucopolysaccharide synthesis. According to Hurley, "Manipulation of a single agent (the nutrient manganese) could, through deprivation, alter the expression of the wild type gene to produce a phenocopy of the mutant. On the other hand, administration of large amounts of the agent (the nutrient manganese) altered the expression of the mutant allele to produce the normal phenotype." In this light, it is useful to consider the following paradigm (modified from Hurley): LEVEL OF NUTRIENT INTAKE Mutant Genotype ---------------------> Mutant Phenotype Normal Genotype ---------------------> Normal Phenotype Mutant Genotype ---------------------> Normal Phenotype Normal Genotype ---------------------> Mutant Phenotype Areas of Research Two general areas of research are appropriate for this RFA, namely molecular/genetic studies of cardiovascular morphogenesis in animal models and small epidemiologic investigations of the role of nutrients in the pathogenesis of human CCVM. It is anticipated that both approaches will yield much needed information on measures that eventually may prevent some cases of CCVM in humans. Successful applications will have hypotheses to direct the course of the research. The molecular/genetic research will test hypotheses regarding potential mechanisms by which a nutritional deficiency or toxicity may produce malformations comparable to human CCVM. Given the existing body of literature on Vitamin A/beta-carotene, studies involving retinoid related genes must address the mechanisms by which decreased RA affects normal morphogenesis of the cardiovascular system. Far less information is available regarding the role of other nutrients in organogenesis. Hence, research on the role of vitamins and trace elements in the pathogenesis of CCVM may be more broadly applied. The use of well-defined animal models, whether naturally occurring or transgenic, is encouraged. Researchers may propose to study gene-nutrient interactions in 'normal' animals fed a nutrient-deficient diet. Investigators also may wish to propose targeted interventions that may correct the abnormal phenotype of an animal model of inherited CCVM. Research resources, such as Keeshond Beagles, which suffer form conotruncal defects, or Yucatan miniature swine, which have a high frequency of ventricular septal defects, may be considered. Similar investigations in humans would be premature and are not appropriate for this RFA. Large new epidemiologic studies are not likely to be feasible with the budgets allotted for grants awarded under this RFA; 'add-on' projects may be proposed, however, to take advantage of existing or planned research programs. Studies that propose to make use of already existing epidemiologic data bases or cohorts with well-defined nutrient intake and pregnancy outcomes are acceptable. However, diagnosis of CCVM in children involved in studies must be performed by a pediatric cardiologist, using appropriate techniques such as echocardiography or angiography to avoid errors due to mis-diagnosis. The following examples of potential studies are given for illustrative purposes only. Investigators are urged to use their own knowledge of the field in preparing their grant applications. o small epidemiologic studies of cases of specific CCVMs for which maternal diets are well-defined o nutritional investigations in animal strains with known predispositions toward specific defects o studies of the role of nutrients in gene expression during cardiovascular development o studies elucidating the role of nutrients in the proliferation and differentiation of progenitor cells o Tissue culture studies of nutrient requirements for synthesis of the cardiac extracellular matrix o elucidation of the role of nutrients in the migration of cells and formation of tissues Exclusions Clinical intervention trials and treatment studies in humans will not be considered responsive to this RFA. Large epidemiologic studies and multiproject studies similar to program project applications will not be accepted. STUDY POPULATIONS INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by December 16, 1994, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the principal investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. C. James Scheirer at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application for PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 240, Bethesda, MD 20892, telephone 301/710-0267. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, to identify the application as a response to this RFA, Check "YES", enter the title "Gene-Nutrient Interactions in the Pathogenesis of Congenital Heart Defects", and the RFA number HL-95-001 on line 2a of the face page of the application. Send or deliver a signed, typewritten original of the application, including the checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to Dr. Scheirer at the address listed under INQUIRIES. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants, otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. Applications must be received by April 21, 1995. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by NIH staff for completeness and responsiveness. Incomplete applications will be returned to the applicant without further consideration. If the application is either late or not responsive to the RFA, NHLBI staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non- competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. The second level of review will be provided by the National Heart, Lung, Blood Advisory Council. Review criteria for this RFA are generally the same as those for unsolicited research grant applications. o the novelty, originality and feasibility of the approach and the adequacy of the experimental design o the competence of the principal investigator and collaborators to accomplish the proposed research, and the commitment and time they will devote to the project o the suitability of the facilities to perform the proposed research, including laboratories, instrumentation and data management systems o the appropriateness of the requested budget and duration for the proposed research o adequate plans for interaction and communication of information and concepts among investigators involved in collaborative studies AWARD CRITERIA Awards made under this RFA to foreign institutions will be made only for research of very unusual merit, need and promise, and in accordance with Public Health Service policy governing such awards. Upon initiation of the program, the Division of Heart and Vascular Diseases will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program and stimulate collaboration. Applicants should request additional travel funds for a one-day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. Applications must fulfill all the eligibility criteria to be considered for funding. The most important criterion in selecting awardees will be the scientific merit as reflected in the priority score. However, factors such as program balance and available funds may enter into selection from among meritorious applications. Timetable Letter of Intent Receipt Date: December 16, 1994 Application Receipt Date: April 21, 1995 Review by NHLBAC: September 1995 Anticipated Award Date: September 1995 INQUIRIES Written and telephone inquiries are encouraged. We welcome the opportunity to clarify any issues or questions from potential applicants. Inquiries regarding programmatic issues may be directed to: Dr. Abby G. Ershow Lipid Metabolism-Atherogenesis Branch National Heart, Lung, and Blood Institute Federal Building, Room 401 7550 Wisconsin Avenue MSC 9050 Bethesda, MD 20892-9050 Telephone: (301) 496-1681 FAX: (301) 496-9882 Dr. Constance Weinstein Cardiac Diseases Branch National Heart, Lung and Blood Institute Federal Building, Room 3C06 7550 Wisconsin Avenue MSC 9050 Bethesda, MD 20892-9050 Telephone: (301) 496-1081 FAX: (301) 480-6282 Direct inquiries regarding review and application procedures, address the leter of intent to, and mail two copies of the application to: Dr. C. James Scheirer Division of Extramural Affairs National, Heart, Lung, and Blood Institute Westwood Building, Room 548B Bethesda, MD 20892 Telephone: (301) 594-7478 FAX: (301) 594-7407 Inquiries regarding fiscal and administrative matters may be directed to: Mr. William Darby Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A11 Bethesda, MD 20892 Telephone: (301) 594-7458 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS The programs of the Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, are identified in the Catalog of Federal Domestic Assistance No, 93.837. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372, or to Health Systems Agency review. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |