Full Text PA-96-011 CELLULAR AND MOLECULAR MECHANISMS OF LYMPHANGIOLEIGMYOMATOSIS NIH GUIDE, Volume 24, Number 42, December 8, 1995 PA NUMBER: PA-96-011 P.T. 34 Keywords: Cardiovascular Diseases Biology, Cellular Biology, Molecular Etiology Pathogenesis 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 lymphangioleiomyomatosis (LAM). The purpose of this program announcement is to stimulate basic research using cellular and molecular approaches to studying the development and subsequent progression of LAM. 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 Lymphangioleiomyomatosis, 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 initiative 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. RESEARCH OBJECTIVES Lymphangioleiomyomatosis (LAM) is a very rare airways and interstitial lung disease that affects almost exclusively young women of childbearing age. The prevalence of the disease is not known but it has been estimated there are a few hundred cases in the United States. The most common symptom of LAM is dyspnea upon exertion and can also include the clinical findings of spontaneous pneumothorax, chylothorax, and hemoptysis. A chest x-ray may show cystic changes, but the most definitive changes are found on chest CT scans where diffuse cystic changes are present uniformly throughout the lung. Histologic examination of lung tissue shows an extensive proliferation of smooth muscle cells of uncertain origin alternating with cystic changes. The abnormal proliferation of smooth muscle, which appears not to be malignant, is seen around airways, blood vessels and lymphatic vessels and may extend into hilar and mediastinal lymph nodes. Approximately 50 percent of LAM patients also have renal and retroperitoneal angiomyolipomas. The life span of these patients is uncertain. The mean survival time following diagnosis was estimated at less than 10 years, but that has now been extended with the recognition that some patients survive more than 20 years. Although there is no clear evidence for a hormonal abnormality, therapy has focused on estrogen reduction because of the population affected and includes oophorectomy, tamoxifen therapy and progesterone therapy. Single lung transplantation has become an established therapeutic option in patients with advanced disease. Recurrence of LAM has been reported in the transplanted lung of two patients raising questions about pathogenesis and suggesting a systemic component is involved. Examples of research topics of interest are listed below. These research topics are intended to provide a perspective of the scope of research that would meet the objectives 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 to the goals. The objective of this program announcement is to encourage basic studies addressing the cellular characteristics and the molecular biology of LAM. There is no animal model of LAM so studies will have to be done using lung tissue and cells originating from LAM patients. It will, therefore, be important to develop immortalized LAM cell lines because of the paucity of patient material available. Because LAM is a proliferative process, studies addressing unique genetic mutations, growth factors, signal transduction systems or transcription factors that might occur in LAM to produce the abnormal proliferative process are encouraged. Also, the possible absence of a growth inhibitory factors, e.g., p53, also needs to be considered. Genetic studies to identify the aberrant gene(s) responsible for the etiology of LAM are also lacking. Knowledge from these types of basic studies is essential before more effective treatment can be developed. Moreover, knowledge learned about LAM may be applicable to other diseases involving hypertrophy of smooth muscle, such as pulmonary hypertension and atherosclerosis. Established technologies and approaches currently being used to study other diseases involving hypertrophy of smooth muscle may be applicable to the study of LAM. The NHLBI is particularly interested in applications that contain hypothesis driven mechanistic studies rather than those proposing only descriptive morphologic studies. Studies that focus primarily on renal angiomyolipomas or retroperitoneal lymphangiomyomas will not be considered responsive to this program announcement. 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 in advance of formal submission. This can be done by telephone, mail, or email. 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. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3032 - MSC-7762, telephone 301/435-0714, email: girg@drgpo.drg.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; 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: Carol E. Vreim, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018 Bethesda, MD 20892-7952 Telephone: (301) 435-0233 FAX: (301) 435-3547 Email: Vreimc@gwgate.nhlbi.nih.gov Carrie P. Hunter, M.D., M.P.H. Office of Research on Women's Health Building 1, Room 202 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 Rockledge 2, Room 7154 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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