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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