CELLULAR AND MOLECULAR MECHANISMS OF PRIMARY PULMONARY HYPERTENSION

Release Date:  January 10, 2000

PA NUMBER:  PA-00-043

National Heart, Lung and Blood Institute

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The goal of this Program Announcement is to promote research in primary 
pulmonary hypertension (PPH) with an emphasis on elucidating a mechanistic 
understanding of the disease.  Studies are encouraged, at the cellular and 
molecular level, to address the basic mechanisms involved in the unique 
vascular remodeling that occurs in PPH, regulation of pulmonary vascular tone 
and the genetic basis of PPH.  Investigators are encouraged to consider a 
scientific approach that integrates new data with existing data in the field 
to define and delineate mechanisms in PPH pathology.  Research to identify 
novel genes or vasoactive mediators important in PPH pathology and 
determination of their functional effects on pulmonary vascular cells, on 
extracellular matrix and on pulmonary vascular tone is a high priority.  
Further, research integrating the relationship between mediators of 
vasoconstriction and pulmonary vascular remodeling is strongly encouraged.  
The ultimate goal is to develop new and effective therapies.

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 (PA), Cellular 
and Molecular Mechanisms of Primary Pulmonary Hypertension, is related to one 
or more of the priority areas.  Potential applicants may obtain a copy of 
"Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this PA may 
not exceed 5 years.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and  detailed instructions and information on Modular Grant 
applications can be found at  
http://grants.nih.gov/grants/funding/modular/modular.htm

RESEARCH OBJECTIVES

PPH is a rare, progressive and often fatal lung disorder for which there is no 
cure.  It is characterized by a sustained elevation of the pressure in the 
pulmonary artery.  This is associated with structural changes in the small 
pulmonary arteries and arterioles resulting in resistance to blood flow.  A 
common vascular remodeling pattern observed in PPH patients is the presence of 
complex, vascular structures called plexiform lesions, that are identified by 
specific histologic features.  The process eventually leads to an enlarged, 
overworked right ventricle that is unable to pump enough blood through the 
lungs resulting in heart failure and death.  The estimates of the incidence of 
PPH range from 1 to 2 people per million in the general public and women are 
predominantly affected.  Based on data from the NHLBI-supported National 
Patient Registry for PPH, it has been estimated that approximately 6% of the 
cases of PPH are due to familial PPH (FPPH).  Recently, interest in pulmonary 
hypertension has escalated due to a rise in the number of cases associated 
with the appetite suppressant drugs, fenfluramine-phentermine (fen-phen) and 
dexfenfluramine (Redux).  The morphologic and clinical features of both 
familial PPH and pulmonary hypertension (PH) associated with the appetite 
suppressant drugs are indistinguishable from those in sporadic PPH.

PPH remains a diagnosis of exclusion, which means that other reasons for the 
pulmonary hypertension, such as chronic lung or heart disease, are not 
present.  It is often diagnosed at an advanced stage when severe symptoms are 
already present.  Thus, identifying initiating events is among one of the 
greatest challenges facing researchers in PPH.  The current consensus is that 
injury to the vascular endothelium and/or smooth muscle cells (SMC) of the 
small pulmonary arteries and arterioles may initiate the disease process.  
Consequently, a dominant theme in PPH research is to understand the underlying 
cellular mechanisms that cause structural changes to the vasculature.  Recent 
data indicate that the plexiform lesions are comprised of endothelial cell 
populations with aberrant growth properties, suggesting that endothelial cells 
and/or their interactions with SMCs play an important role in PPH vascular 
remodeling.  Further, impaired K+ channel expression and function in SMCs 
isolated from PPH patients has been implicated in dysfunctional regulation of 
free cytosolic Ca2+ concentration, triggering vasoconstriction and SMC 
proliferation.  Thus, identifying distinct cell populations, expression of 
novel genes or unique signal transduction pathways in PPH vascular cells is 
needed to understand mechanisms causing the disease.  In addition, components 
of the extracellular matrix, such as elastase, can be activated and lead to 
changes in vessel wall structure.  Thus, additional research to understand the 
interactions of endothelial cells, SMCs and the extracellular matrix in PPH is 
necessary.  

It has been suggested that the pathogenesis of PPH is a consequence of an 
imbalance between vasoconstricting and vasodilating mediators.  Several 
imbalances have been proposed, for example, a decrease in prostacyclin, 
possibly attributed to a reduced expression of prostacyclin synthase, a 
decrease in nitric oxide (NO) levels or an increase in thromboxane or 
endothelin.  The importance of vasoactive substances in modulating the 
vasculature in PPH has been suggested; however, whether common signaling 
pathways exist for their mechanisms of action and the functional effects on 
endothelial cells, vascular SMCs and the maintenance of vascular tone requires 
additional research.  Further, additional research is necessary to determine 
if families of vasoactive mediators exist that can elicit similar effects on 
the vasculature.  Finally, the effects of various mediators released from 
blood cells on the pulmonary vasculature is incompletely understood.  
Serotonin released from blood platelets may cause PH through influences on 
SMCs of pulmonary vessels.  ATP, released from red blood cells, leads to 
increases in NO from pulmonary endothelial cells that may effect vascular 
tone.  Additional research is needed to understand the mechanism of action of 
these and other components from blood cells and their interactions with 
pulmonary vascular cells.

One hypothesis that has been suggested for the pathogenesis of PPH is that the 
initial endothelial cell injury leads to changes in the hemodynamic condition 
creating the appropriate local environment for the development of vascular 
remodeling that occurs in the disease state.  Investigators are encouraged to 
integrate research that explores the relationship between mediators of 
vasoconstriction and cellular changes that occur in vascular remodeling, such 
as the interactions between mediators released from endothelial cells with the 
underlying SMCs and their resulting vasoactive effects on the pulmonary 
vasculature.  

Improved animal models of PPH remain an important need.  Some exceptional 
descriptive studies have led to the questions being addressed today with 
animal models.  Transgenic and knockout mice are being developed as more genes 
are implicated in the pathogenesis of PPH.  The physiological responses in 
genetically manipulated animals will likely provide useful tools to understand 
the pathogenesis of the disease and to develop novel therapies for PPH.  
Various animal models of PH, induced with hypoxia or monocrotaline, have 
contributed to our understanding of the pathogenesis of PPH.  Although these 
models currently serve as useful tools, they do not completely duplicate PPH 
cellular changes and physiology, therefore, further optimization of good 
animal models are critical for future PPH research. 

The identification and characterization of the gene for familial PPH (FPPH) 
will likely lead to diagnostic accuracy, identification of carriers, future 
avenues for therapeutic interventions and an effective route to establish a 
central mechanism for PPH.  The frequency of FPPH may be underestimated since 
affected individuals in many families are few (low penetrance) and the passage 
of the gene to individuals who never develop the disease may occur (incomplete 
penetrance).  The familial form is inherited as an autosomal dominant trait.  
There has been significant progress made in identifying the gene, but 
additional research is still required to further narrow the genetic region.  
In addition, should the gene for PPH be a gain-of-function gene, then 
transgenic mice overexpressing this gene would be an invaluable tool.  

The research topics identified above are examples of studies that would meet 
the objectives of this announcement.  It is not required that all or any of 
the topics be included; investigators are encouraged to consider other topics 
that are relevant to the goals of this program, which is to uncover the 
mechanisms  involved in PPH with the goal of designing new and effective 
therapies. 

To be responsive to this announcement, studies must be conducted on patients 
diagnosed with PPH, on material obtained from PPH patients or on novel animal 
or cellular models relevant to PPH.  Patient material could include isolated 
cells, blood samples, lung tissue from patients receiving transplants or 
biopsy/autopsy specimens.  Studies using animal or cellular models must 
provide evidence that it is relevant to PPH.  Studies including other forms of 
PH may be included for comparison purposes provided that the major focus of 
the application is on understanding the mechanisms of PPH.


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 policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

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 in the NIH Guide for Grants and Contracts, Vol. 23, 
No. 11, March 18, 1994 available on the web at the following URL address:  
http://grants.nih.gov/grants/guide/notice-files/not94-100.html
 
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact the program staff listed under
INQUIRIES with any questions regarding their proposed project and the goals of 
this PA.  This may be done by telephone, mail or E-mail.

Applications are to be submitted on the grant application form PHS 398 (rev. 
4/98) 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 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: GrantsInfo@nih.gov.

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact the 
Institute or Center (IC) program staff before submitting the application, 
i.e., as plans for the study are being developed.  Furthermore, the 
application must obtain agreement from the IC staff that the IC will accept 
the application for consideration for award.  Finally, the applicant must 
identify, in a cover letter sent with the application, the staff member and 
Institute or Center who agreed to accept assignment of the application.  

This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment.  Refer to the NIH 
Guide for Grants and Contracts, March 20, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $250,000 per year. (Applications that request 
more than $250,000 direct costs in any year must follow the traditional PHS 
398 application instructions.)  The total direct costs must be requested  in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total 
Direct plus Facilities and Administrative (F&A) costs] for the initial budget 
period Items 8a and 8b should be completed indicating the Direct and Total 
Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398. It is not required and will not be accepted with the 
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not required and 
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.) At the top of the page, enter the total direct costs requested for 
each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
 salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the nearest 
$1,000. List the individuals/organizations with whom consortium or contractual 
arrangements have been made, the percent effort of key personnel, and the role 
on the project. Indicate whether the collaborating institution is foreign or 
domestic. The total cost for a consortium/contractual arrangement is included 
in the overall requested modular direct cost amount.  Include the Letter of 
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual's qualifications for a specific 
role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for all 
key personnel, following the instructions below. No more than three pages may 
be used for each person. A sample biographical sketch may be viewed at:  
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the type 
of agreement and the date. All appropriate exclusions must be applied in the 
calculation of the F&A costs for the initial budget period and all future 
budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review. 

The title and number of the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the 
Checklist, and five signed photocopies in one package to:

CENTER FOR SCIENTIFIC REVIEW
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 PHS referral 
guidelines.  Applications will be evaluated for scientific and technical merit 
by an appropriate scientific 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

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

Additional scientific/technical merit criteria specific to the objectives of 
the PA and the mechanism used must be included if they are to be used in the 
review.

AWARD CRITERIA

Applications will compete for available funds with all other recommended 
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

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Susan Garfinkel, 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: garfinks@nih.gov

Direct inquiries regarding fiscal matters to:

Ray Zimmerman
Grants Operations Branch
National Heart, Lung and Blood Institute
6701 Rockledge Drive, 
Bethesda, MD  20892
Telephone:  (301) 435-0171
FAX: (301) 480-3310
Email: zimmermr@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 NIH grants policies and Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  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, and 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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