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 301/435-0714, 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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