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
https://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: gaild@nhlbi.nih.gov
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: clarka@nhlbi.nih.gov
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: alston@nhlbi.nih.gov
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: clarka@nhlbi.nih.gov
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 https://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
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
https://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
https://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:
https://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: ClarkA@nhlbi.nih.gov
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
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a
complete copy of the updated Guidelines are available at
https://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
https://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
https://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
https://grants.nih.gov/grants/stem_cells.htm and at
https://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
https://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 https://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.