Full Text PA-95-075 TRANSIT FROM CARDIAC HYPERTROPHY TO OVERT HEART FAILURE NIH GUIDE, Volume 24, Number 25, July 14, 1995 PA NUMBER: PA-95-075 (inactive per NOT-HL-00-003) P.T. 34 Keywords: 0705037 Cardiovascular Diseases Biology, Cellular Biology, Molecular 0765014 National Heart, Lung, and Blood Institute PURPOSE This program announcement solicits applications for research on a molecular and cellular approach to elucidation of the signaling mechanisms that coordinate the events that lead to deterioration of cardiac structure and function. Appropriate studies may include mechanisms of action of mediators derived from myocardial, interstitial, endothelial, endocrine, or immune cells and the respective receptors for those mediators, as well as the factors that affect altered gene expression of these mediators and their receptors. 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 PA, Transit from Cardiac Hypertrophy to Overt Heart Failure, is related to the priority area of heart disease and stroke. 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 foreign and domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. MECHANISM OF SUPPORT Research support mechanisms include traditional research project grants (R01) and FIRST (R29) awards. Traditional research project grants (R01) provide support for up to five years. Applications for FIRST (R29) awards must request support for five years and are limited to $350,000 in direct costs over the entire project period. RESEARCH OBJECTIVES Congestive heart failure (CHF) is estimated to affect three million people in the United States. It is the final common pathway of a variety of primary cardiovascular disease entities, such as coronary artery disease, hypertension, valvular heart disease, genetic disorders, diabetes and the sequelae of infection or toxin exposure, among others. Hospitalizations and mortality from CHF have increased steadily since 1968, despite the overall improvement in mortality from cardiovascular disease. Heart failure is now the underlying cause of death in over 39,000 persons annually. In 1992, it was the first listed diagnosis in 822,000 persons and is the most common hospital discharge diagnosis in persons over 65 years of age. The incidence of death from CHF is 1.5 times as high in black Americans as in whites. The estimated direct economic cost of CHF in the United States is reported to be $10.2 billion annually. At present, the only cure for end-stage CHF is cardiac transplantation. One fundamental question that needs to be answered before progress can be made in the prevention and treatment of heart failure is how the compensated, hypertrophied heart progresses to failure. In recent years, research on the natural history of heart failure has benefitted from the application of cell and molecular biology techniques. Physiological studies on the development of pathological hypertrophy have led to the view that hypertrophy is compensatory, but while providing a short-term adaptive response to maintain cardiac output, it eventually becomes maladaptive. Studies have shown that the mechanism of hypertrophic growth involves remodeling of all cardiac tissue compartments: myocytes, matrix, and vasculature, and is associated in cardiac myocytes with a molecular expression profile bearing much similarity to the fetal phenotype. Mechanisms such as the immediate/early gene response and peptide growth factor expression have been implicated in this molecular switching, but little is known about their role in the overall ventricular remodeling that occurs in vivo. A variety of studies suggest that the physiological function of the myocardium is modified through complex cross-talk among vascular, interstitial and myocyte compartments of the heart. Thus, locally produced mediators can act in autocrine and paracrine fashions to modify function or induce cell death. Research is required to understand the mechanisms of this cross-talk which has important consequences in the transition to heart failure. For example, several studies suggest a role for the endogenous vascular peptide, endothelin. Experiments employing the rapid pacing model demonstrated a two-fold increase in circulating endothelin that correlated well with known physiological markers of CHF. Interestingly, elevated circulating endothelin levels have also been reported in human heart failure. Receptors for endothelin have been identified in cultures of rat cardiac myocytes, and the peptide has been demonstrated to have potent positive inotropic activity in rat ventricular myocytes. Angiotensin II (AII) levels are elevated in CHF. This potent vasoconstrictor peptide is produced in renal tissue and activated both systemically and in myocardial tissue by angiotensin converting enzyme (ACE). The active peptide is also a secretogogue for endothelin. A recent report demonstrates that the AII-stimulated release of endothelin from human endothelial cells is inhibited by atrial natriuretic peptide (ANP). In the adult human, ANP is normally made and secreted only by atrial myocytes and ventricular conduction cells. ANP synthesis and secretion from ventricles is stimulated in the failing heart. A recent study has correlated the expression of ANP in the ventricle with increasing end-diastolic pressure or volume and worsening New York Heart Association functional class. The release of ANP is also stimulated by endothelin. Thus angiotensin, endothelin and ANP may be partners in a feedback loop which is important in determining the functional status of the myocardium. Research is needed to understand how these factors mediate the changes in vascular impedance and fluid volume in the presence of a failing heart. Other lines of investigation suggest that the immune system, acting through cells of the myocardium, may play a role in the transition to heart failure but how the immune system is recruited and how it mediates maladaptive cardiac growth and altered function is not understood. Similarly, such factors as impairment of alpha and beta adrenergic receptor function, and altered phospholamban and heat shock protein expression are associated with heart failure but the stimulus to effect these changes is not understood. Genetically altered animals offer much promise to study the basic mechanisms responsible for heart failure and to develop therapy. Information now available on genes involved with abnormal cardiac growth may be utilized to develop new models. Discovery of new genes altered in the transition to heart failure may also be the source of exciting approaches. Proposed Research Examples of studies that could be included under this initiative are listed below. The list is not meant to be exhaustive, and many other types of studies would certainly be appropriate. o Elucidation of the mechanisms underlying the growth response of the overloaded heart. o Identification of the origins of the peptide growth factors, TGF-betaF, alpha-FGF and beta-FGF and their role in ventricular wall remodeling in the adult. o Elucidation of the mechanisms whereby ACE inhibitors lower peripheral vascular resistance in heart failure patients and appear to reverse hypertrophy of damaged myocardium. o Elucidation of the mechanisms whereby beta-blockers have beneficial effects on myocardial remodeling. o Investigations of the pathophysiological consequences of immune cytokines in heart failure. o Studies of the interactions between cytokine action, neuroendocrine activation, and growth abnormalities in the failing heart should be investigated. o The development and use of genetically altered animals to explore the molecular and physiological factors and processes responsible for heart failure and to devise and test new therapeutic modalities. While it is recognized that heart failure commonly occurs in the setting of neuroendocrine excess, applications that focus exclusively on the classical role of the neuroendocrine system in heart failure are not encouraged. However, studies of the effects of the neuroendocrine system on cellular and molecular processes in the failing myocardium would be responsive. Strategies that employ neonatal cardiac myocytes must demonstrate a clear relationship to heart failure beyond descriptive similarities between the onset of cardiac hypertrophy in the adult and fetal cardiac gene expression in order to be considered responsive; such studies, for example, could highlight differences in the growth responses to overload of proliferating and terminally differentiated myocytes. 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 20, 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. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits 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, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD 20892, telephone 301/710-0267. The title and number of the program announcement must be typed in Section 2a on the face page of the application. Applications for the FIRST award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST award (R29) applications submitted without the required number of reference letters will be considered incomplete and returned without review. The completed original application and five legible copies must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures. Following scientific and technical review, the applications will receive a second-level review by the appropriate national advisory council. Applications that are complete and responsive to the program announcement will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria o scientific, technical or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to that IC. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Isabella Liang, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Two Rockledge Center Suite 9044 6701 Rockledge Drive Bethesda, MD 20892-7940 Telephone: (301) 435-0520 FAX: (301) 480-1335 Email: ISABELLA_LIANG@NIH.GOV Direct inquiries regarding fiscal matters to: William W. Darby Grants Operations Branch National Heart, Lung, and Blood Institute Two Rockledge Center Suite 7128 6701 Rockledge Drive Bethesda, MD 20892-7128 Telephone: (301) 435-0177 FAX: (301) 480-3310 Email: WILLIAM_DARBY@NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants' policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routing 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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