Full Text PA-97-022 CELLULAR AND MOLECULAR MECHANISMS OF PRIMARY PULMONARY HYPERTENSION NIH GUIDE, Volume 26, Number 1, January 10, 1997 PA NUMBER: PA-97-022 P.T. 34 Keywords: Biology, Cellular Biology, Molecular Hypertension 0705048 National Heart, Lung, and Blood Institute Office of Research on Women's Health Office of Rare Disease Research PURPOSE The National Heart, Lung, and Blood Institute (NHLBI), the Office of Research on Women's Health, and the Office of Rare Disease Research invite qualified researchers to submit applications for research project grants to investigate the cellular and molecular mechanisms of the etiology and pathogenesis of primary pulmonary hypertension (PPH). The purpose of this program announcement is to stimulate basic research using cellular and molecular approaches to studying the development and subsequent progression of PPH. Applicants are required to study patients diagnosed with PPH or to use materials of patient origin. 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 Program Announcement, Cellular and Molecular Mechanisms of Primary Pulmonary Hypertension, is related to the priority area of chronic disabling diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-004730-01) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/512-1800). ELIGIBILITY REQUIREMENTS Applications for research grants may be submitted by foreign and domestic, public and private, for-profit and non-profit organizations, such as universities, colleges, hospital, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women and persons with disabilities are encouraged to apply. MECHANISM OF SUPPORT The primary mechanisms for support of this program announcement are the research project grant (R01) and the FIRST award (R29). Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of awards will vary also. Primary pulmonary hypertension (PPH) is a rare disease of unknown cause characterized by abnormally high pressure in the pulmonary artery. The first case of unexplained pulmonary hypertension was described in the literature by Romberg in 1891. In 1951 Dresdale and associates described a series of 39 patients with unexplained pulmonary hypertension and coined the term primary pulmonary hypertension to describe this condition. The diagnostic criteria currently used, as developed by the NHLBI national patient registry, is a mean pulmonary artery pressure of 25 mm Hg at rest or 30 mm Hg during exercise in the absence of other chronic lung or heart disease. The incidence of PPH is unknown, but estimates range from 1 to 2 per million in the general population. PPH can occur in individuals of all ages and both genders, but it appears to affect predominately women in their third and fourth decades of life. The diagnosis of PPH is difficult as there are no specific signs or symptoms in the early stages of the disease. The time from early symptoms to diagnosis is often 2 to 3 years or longer. The most common presenting symptom is dyspnea; other common symptoms are fatigue, chest pain and near syncope. The pathogenesis of PPH is not clearly understood. It is also not known whether PPH is a single disease or a variety of diseases with the same common end stage lung condition. The increased vascular resistance seen in PPH has been attributed to two major factors: 1) vasoconstriction and 2) thickening or remodeling of the vascular arterial wall. There is also a tendency for blood clots to form within the small vessels. Many questions remain unanswered about the etiology and pathogenesis of primary pulmonary hypertension. It has been suggested that abnormalities in pulmonary vascular endothelial function may play a major role in initiating the process that ultimately leads to PPH. Studies in PPH patients have shown an imbalance in the ratio of the metabolites of prostacyclin and thromboxane. Other studies have shown an impaired synthesis of the endothelial-derived vasodilator nitric oxide, that could be due to a reduced level or activity of nitric oxide synthetase. Endothelin, a potent endothelial-derived vasoconstrictor, has been found to be at abnormally high levels in PPH patients. Other mediators that have been suggested to have a role in PPH are serotonin and angiotensin. More studies are needed to determine whether the abnormal levels of these mediators are the cause or result of the hypertensive arteriopathy seen in PPH patients. A number of cytokines and growth factors, including interleukin-1 and interleukin-6, transforming growth factor, and vascular endothelial growth factor have all been implicated in the thickened arterial vascular wall seen in PPH. The role of inflammatory cytokines and growth factors in the development and progression of PPH needs to be better defined. Also, the enhanced thrombotic state, that may be related to endothelial dysfunction or platelet abnormalities, needs further study. Another area of interest is that of calcium and potassium transport in vascular smooth muscle cells. Immune dysfunction has also been postulated to play a role in PPH. There is evidence to suggest that susceptibility to PPH may be influenced by products of the major histocompatibility complex. There is no cure for PPH and treatment is limited. The mean survival time of the registry patients was 2.8 years, but this has been extended in some patients using newer treatment modalities. The most widely used vasodilators are the calcium channel blockers, nifedipine and diltiazem, which produce sustained improvement in 25 to 30 percent of patients. Recently, epoprostenol (prostacyclin) became available for patients who do not respond to oral vasodilators but, unfortunately, the drug has to be delivered by continuous intravenous infusion. In a randomized clinical trial, it has recently been shown that epoprostenol improved hemodynamics, exercise tolerance, quality of life and survival in patients with New York Heart classification III and IV. More recently a few patients are apparently having beneficial effects from chronic inhalation of nitric oxide. The only other therapy available is lung transplantation, but that also has many disadvantages, including shortage of donor organs and acute and chronic rejection and infection. Several factors have been associated with the development of pulmonary hypertension, that has clinical and pathologic features similar to that of primary pulmonary hypertension. These factors include portal hypertension, Raynaud's disease, infection with human immunodeficiency virus, and the use of diet suppressants, including aminorex and fenfluramine. Since only a small percentage, 0.5 to 2 percent, of the individuals exposed to these factors actually develop pulmonary hypertension, it has been suggested that a predisposition, perhaps genetically determined, must be present for PPH to develop in response to a stimulus. Approximately 6 to 10 percent of PPH cases are familial, which clearly involves a genetic basis. The purpose of this program announcement is to stimulate basic studies of the cellular and molecular mechanisms involved in the development and pathogenesis of primary pulmonary hypertension. Knowledge from these types of basic studies should be helpful in designing more effective treatment for PPH. The research topics identified above are examples of studies that would meet the goals of this program announcement. It is not required that all or any of these topics be included; investigators are encouraged to consider other topics that are relevant this program. SPECIAL REQUIREMENTS To be responsive to this program announcement the studies must be conducted in patients diagnosed with PPH or on materials obtained from PPH patients. This could include blood samples, lung tissue from patients receiving transplants or biopsy/autopsy specimens. Although studies of other forms of pulmonary hypertension can be included for comparison purposes, the major focus of the application must be on PPH. Studies in animal models of pulmonary hypertension will not be considered responsive to this announcement. Applications that propose descriptive morphologic studies and do not contain any hypothesis driven mechanistic studies will not be acceptable. 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 new 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 of March 18, 1994, Volume 23, Number 11. Investigators also may obtain copies of the policy form from the program staff listed under INQUIRIES. Program Staff may also provide additional relevant information concerning the policy. (NOTE: When the proposed study involves a gender specific study or a single or limited number of minority population groups, this should also be stated to inform reviewers.) APPLICATION PROCEDURES Researchers who are considering preparing an application in response to this program announcement are invited, but not required, to discuss their project and possible grant mechanisms with NHLBI staff listed under INQUIRIES in advance of formal submission. This may be done by telephone, mail, or E-mail. The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants and will be accepted at the standard application deadlines as indicated in the application kit. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed under INQUIRIES. The PA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. FIRST (R29) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The original and five copies must be mailed to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight 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 in accordance with the standard NIH peer review procedures. Applications that are complete 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; o the initial review group will also examine the proposed study for the protection of human subjects and the safety of the research environment. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council. AWARD CRITERIA Applications will compete for available funds with all other approved applications. 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 Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dorothy B. Gail, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC-7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: Gaild@gwgate.nhlbi.nih.gov Carrie P. Hunter, M.D., M.P.H. Office of Research on Women's Health National Institutes of Health Building 1, Room 201, MSC-0161 Bethesda, MD 20892-0161 Telephone: (301) 402-1770 FAX: (301) 402-1798 Email: Hunterc@od1tm1.od.nih.gov Stephen Groft, Pharm.D. Office of Rare Disease Research National Institutes of Health 7550 Wisconsin Avenue, Room 618 Bethesda, MD 20892 Telephone: (301) 402-4336 FAX: (301) 402-0420 Email: Grofts@nih.gov Direct inquiries regarding fiscal matters to: Ray Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC-7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: Zimmermr@gwgate.nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.838. 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 174. 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 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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