MOLECULAR TARGETS AND INTERVENTIONS IN PULMONARY FIBROSIS
 
RELEASE DATE:  March 14, 2002

RFA:  HL-02-020
 
National Heart, Lung, and Blood Institute (NHLBI) 
 (http://www.nhlbi.nih.gov/)

LETTER OF INTENT RECEIPT DATE:  August 23, 2002

APPLICATION RECEIPT DATE:  September 20, 2002
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The purpose of this Request for Applications (RFA) is to support a 
broad research effort to develop new therapeutic approaches for 
pulmonary fibrosis (PF).  The primary objective is to support 
applications to discover and validate molecular targets for interfering 
with fibrogenesis in PF in humans and identify agonists or antagonists 
that interact with the previously or newly identified targets to 
attenuate, halt, or reverse the fibrotic process.  Applicants must plan 
to utilize human PF patients or tissue to identify targets and agents 
that interact with them.

RESEARCH OBJECTIVES

PF is a chronic diffuse interstitial lung disease of unknown cause, 
characterized pathologically by inflammation and fibrosis of the lung 
parenchyma.  Prognosis is poor with a fifty per cent mortality at five 
years after diagnosis and considerable morbidity during those years.  
Previous investigations have documented the role for inflammation in 
the pathogenesis of PF and current therapeutic strategies are aimed at 
suppressing the inflammation.  Data generated over the past decade also 
have established the concept that the molecular processes underlying 
the fibrogenesis component may represent a new opportunity for 
therapeutic intervention.

Attempts to treat PF have for the most part consisted of anti-
inflammatory drugs, almost exclusively steroids.  The effectiveness of 
steroids is variable and can be associated with significant side 
effects.  Although recent findings suggest interferon-gamma may prove 
to have beneficial effects, alternative approaches to treatment are 
needed that have the advantages of reduced cost, increased specificity, 
and reduced side effects.  

One approach to new treatments would be to identify new agents that 
interact with previously identified molecules or pathways (e.g., TGF-
Beta, growth factors, proteinases, apoptosis, myofibroblast 
differentiation and proliferation, signaling pathways, collagen 
synthesis) that are known to be involved in the development of 
fibrosis.  Such agents could range from small molecules to vaccines.  
One recent example of this approach has been to focus on 5-lipoxygenase 
as a target for intervention in PF.  This RFA is meant to support 
applications designed to identify agents that interact with such 
previously identified molecular targets to inhibit progression or 
reverse fibrosis in PF patients.

There are also potentially new molecular targets to be discovered, 
which if agonists or antagonists existed, could provide new approaches 
to treatment of PF.  There are many new powerful technologies and 
resources that are available to look for differences between normal and 
fibrotic lung tissue (e.g., levels of specific proteins or signaling 
patterns) and thus could identify potential targets for intervention.  
Such technologies include laser capture microdissection, microarrays, 
and mass spectroscopy analysis of proteins, which could be used to 
identify molecular targets in the pathways leading fibrotic lung 
disease.  This RFA is meant to support applications designed to 
identify new targets for intervention in PF, using new technologies.  

Although there may be considerable data on a cellular or molecular 
pathway"s involvement in the pathogenesis of PF, the point of greatest 
vulnerability in the pathway and therefore, perhaps the optimal point of 
drug attack, may not be clear.  This RFA is intended to support 
identification of a target(s) and validation of its role in the 
development of pulmonary fibrosis.  Applicants may address targets 
related to cellular or molecular pathways known to be involved in the 
pathogenesis of PF, or identify targets in pathways previously unknown 
to be related to PF.  

Investigators may use their own creativity in defining an approach.  For 
example, some may prefer to use a genetic, structural biology or 
molecular biology approach to target identification/validation employing 
information from genetic studies or studies of pathways, whereas others 
may prefer to identify the function of a cellular target after first 
finding the target as a result of exploring binding patterns of natural 
products or other ligands to normal and fibrotic tissue.  

MECHANISM OF SUPPORT
 
This RFA will use National Institutes of Health (NIH) Individual 
Research Project Grant (R01) award mechanism.  As an applicant you will 
be solely responsible for planning, directing, and executing the 
proposed project.  This RFA is a one-time solicitation.  Future 
unsolicited, competing-continuation applications based on this project 
will compete with all investigator-initiated applications and will be 
reviewed according to the customary peer review procedures.  The 
anticipated award date is July 1, 2003.

This RFA uses "Just-In-Time" (JUST) concepts.  It also uses the modular 
budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  

FUNDS AVAILABLE
 
The NHLBI intends to commit approximately $3,000,000 in FY 2003 to fund 
4 to 6 new grants in response to this RFA.  An applicant may request a 
project period of up to 4 years and a budget for direct costs up to 
$500,000 per year.  Because the nature and scope of the research 
proposed may vary, it is anticipated that the size of each award will 
also vary.  Although the financial plans of the NHLBI provide support 
for this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of 
meritorious applications.

ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations, 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories, 
o Units of State and local governments,
o Eligible agencies of the Federal government,  
o Domestic or foreign.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   
 
SPECIAL REQUIREMENTS

Grantees" Meetings

Upon initiation of the program, the NHLBI will sponsor annual meetings 
to encourage exchange of information among investigators, who 
participate in this program.  In their budgets, applicants should 
include funds for annual one-day grantees" meetings, most likely in 
Bethesda, Maryland.  Applicants should also include a statement in their 
applications indicating their willingness to participate in these 
meetings.  The first such meeting likely will take place within 3 months 
of award. 

Cooperation Among Grantees

Because of the possible difficulty of obtaining sufficient human tissue 
with which to conduct the studies, the awardees must include in their 
application, how many PF patients from whom they expect to be able to 
obtain tissue, how the tissue is obtained and subsequently processed, 
and a willingness to participate in a meeting to determine how to 
standardize tissue collection so that it is usable by all awardees.  
Applicants must indicate in their application their willingness to share 
human tissue and data with other awardees.  Such sharing of tissue will 
also facilitate identification and evaluation of different potential 
targets in the same tissue from the same patient.  Applicants should 
include sufficient funds to cover the cost of shipping tissues.

Exclusions

In order to be responsive to this RFA, applications must propose studies 
involving the use of human PF patients or patient tissue.  Applications 
whose primary focus is development of an animal model of PF will not be 
considered responsive.

In addition, in order to be responsive, applications must contain each 
of the following items:

o a statement of willingness to participate in an initial meeting to 
standardize collection, processing, and shipping of human PF tissue 
o a statement of willingness to share human PF tissue and data with 
other awardees
o a strategy for identifying agonists or antagonists for a target 
molecule in the fibrotic pathway
o a strategy for testing the impact of the interaction of an agent with 
the target on PF

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Dorothy B. Gail, Ph.D.
Director, Lung Biology and Diseases Program
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:  [email protected]

o Direct your questions about peer review issues to:

Anne P. Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs 
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, Maryland  20892-7924 (20817 for express/courier service) 
Telephone:  (301) 435-0270 
Fax:  (301) 480-0730 
Email:  [email protected]

o Direct your questions about financial or grants management matters 
to:

Teneshia G. Alston
Grants Operations Branch
Division of Extramural Affairs 
National Heart, Lung, and Blood Institute 
2 Rockledge Centre,  Room 7154
Bethesda, Maryland  20892-7926 
Telephone:  (301) 435-0150 
FAX:  (301) 480-3310 
E-mail:  [email protected]

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information 
that it contains allows IC staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

Anne P. Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs 
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, Maryland  20892-7924 (20817 for express/courier service) 
Telephone:  (301) 435-0270 
Fax:  (301) 480-0730 
Email:  [email protected]

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: [email protected].

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
must be submitted in a modular grant format.  The modular grant format 
simplifies the preparation of the budget in these applications by 
limiting the level of budgetary detail.  Applicants request direct 
costs in $25,000 modules.  Section C of the research grant application 
instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked.  The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist, and three 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)
 
At the time of submission, two additional copies of the application as 
well as all five collated sets of Appendix material must be sent to:
 
Anne Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7178, MSC 7924
Bethesda, MD  20892-7924 (20817 for express/courier service)
Telephone:  (301) 435-0270
FAX:  (301) 480-0730
Email:  [email protected]
 
APPLICATION PROCESSING: Applications must be received by the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review.
 
The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude 
the submission of substantial revisions of applications already 
reviewed, but such applications must include an Introduction addressing 
the previous critique.

Principal investigators should not send supplementary material without 
first contacting the Scientific Review Administrator (SRA).  The SRA 
will be identified in the letter sent to you indicating that your 
application has been received.  If you have not received such a letter 
within three weeks after submitting the application, contact Dr. Anne 
Clark at the address listed under Inquiries.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NHLBI.

Incomplete applications will be returned to the applicant without 
further consideration.  And, if the application is not responsive to 
the RFA, CSR staff may contact the applicant to determine whether to 
return the application to the applicant or submit it for review in 
competition with unsolicited applications at the next appropriate NIH 
review cycle.

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the (IC) in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a second level review by the National Heart, Lung, and Blood 
Institute National Advisory Council.

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 your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application"s overall score, weighting them 
as appropriate for each application.  Your 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, 
you 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 your study address an important problem?  If 
the aims of your application are achieved, how do they advance 
scientific knowledge?  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?  Do you acknowledge potential problem areas and 
consider alternative tactics?

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

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

(5) ENVIRONMENT:  Does the scientific environment in which your 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.

(6) ACCESS TO PF PATIENTS:  Access to adequate human PF patients or 
tissue to conduct the studies proposed.	

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  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.

o INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated.  (See 
Inclusion Criteria included in the section on Federal Citations, below)

o DATA SHARING:  The adequacy of the proposed plan to share data. 

o BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: August 23, 2002
Application Receipt Date:  September 20, 2002
Peer Review Date:  February 2003 
Council Review:  May 2003
Earliest Anticipated Start Date:  July 1, 2003

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  It is the 
policy of the NIH that women and members of minority groups and their 
sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating 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 clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2
001.htm.  The amended policy incorporates: the use of an NIH 
definition of clinical research, updated racial and ethnic categories 
in compliance with the new OMB standards, clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398, and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable, and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:  The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for research 
involving human subjects.  You will find this policy announcement in the 
NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).  It is the responsibility of the applicant to 
provide the official NIH identifier(s)for the hESC line(s)to be used in 
the proposed research.  Applications that do not provide this 
information will be returned without review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom of 
Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application.  In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations.  Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites.  Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas.  This RFA is related to one or more of the priority areas.  
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.838 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and administered under NIH grants policies described 
at http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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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