RELEASE DATE:  July 28, 2003
RFA:  HL-04-009
National Heart, Lung, and Blood Institute (NHLBI)




o Purpose of this RFA
o Research Objectives
o Mechanism(s) 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


The purpose of this Request for Applications (RFA) is to initiate a broad 
research effort to support novel work on the inciting immunopathogenic 
mechanisms leading to nontuberculous granulomatous inflammation in the lungs 
pertaining to sarcoidosis.  Investigators new to sarcoidosis research are 
particularly encouraged to develop projects in this area.  Research involving 
human tissues or biological samples is encouraged.

Sarcoidosis, an illness of unknown cause, usually affects the respiratory tract, 
but often involves many other organs as well.  Although many patients have only 
intrathoracic illness, others unpredictably can experience a severe multi-organ 
disease.  However, the unknown inciting stimulus can elicit an immunologic host 
response, the non-caseating granuloma, in almost every organ.  While this 
stimulus can be widespread throughout the body, the biology of the disease is 
variable.  For sarcoidosis, the cause remains unknown, its course is variable, 
and treatment (usually with corticosteroids) is nonspecific and has side 
effects.  Sarcoidosis remains an important public health issue.  Its incidence 
in the United States is approximately 10 per 100,000 in the white population 
but higher (35 per 100,000) among Blacks.  In the US about 40,000 people are 
affected with sarcoidosis.  Moreover, the illness is more severe in those 
diagnosed at a more advanced radiologic stage of lung involvement and 
impairment of forced vital capacity, in persons of low socioeconomic status who 
are medically underinsured, and in Blacks.

The NHLBI convened a working group on "Future Research Directions in 
Sarcoidosis" in August 2002.  The group advised that in addition to seeking the 
etiology of sarcoidosis and determining susceptibility factors, the initial 
components in the innate and/or adaptive immune pathways that affect lung lymph 
nodes or tissue in early disease must be identified.  The immunopathogenesis of 
granulomatous inflammation similar to that found in sarcoidosis needs to be 
studied in relevant animal models and in human tissues to identify therapeutic 
targets appropriate for clinical trials.  This approach would include the role 
of predisposing factors, the immune components involved in the formation of 
granuloma and the defective regulatory immune response (TH1 pathway) all of 
which need to be evaluated with innovative projects.  

The research objectives and scope of this initiative are to: 1) solicit and 
support innovative approaches for producing granulomatous inflammation in the 
lungs that resembles the histopathological appearance of sarcoidosis and 2) 
encourage investigators working in other areas of research to bring novel 
perspectives and expertise to this field.  Animal models or human sarcoidosis 
tissue may be utilized.  High risk, high impact projects are sought that have 
potential to significantly increase present understanding of the mechanisms 
that induce granulomatous lung changes.  Studies on the role of innate immunity, 
antigen presentation, dendritic cell antigen processing, T-cell regulation and 
hypersensitivity in granulomatous lung inflammation are pertinent.  The 
characterization of specific immunoregulatory cytokines in the setting of 
chronic granulomatous lung inflammation is also of interest.  Moreover, murine 
models of inflammatory bowel disease, if they have associated lung inflammation, 
might pertain to mechanisms relevant for sarcoidosis.

Examples of innovative lung projects to evaluate new concepts of granulomatous 
lung inflammation may include, but are not limited to, research in the 
following areas:

o mechanistic basis for different immune responses induced by systemic versus 
mucosal routes;
o identification and characterization of promising antigen-presenting cell 
molecular targets and T-cell pathways;
o detection of airway antigens – non-peptide self antigens, alloantigens, 
allergens, and relevant infectious agents;
o novel technologies to assess innate or adaptive immunity for T or B cell 
o development or application of cell and tissue engineering methods to induce 
immune tolerance; 
o characterization of novel, antigen-specific immunosuppressive cell types.

Studies with tissue or biologic samples from sarcoidosis patients are 
encouraged, and may include:

o analysis of bronchoalveolar fluid for relevant cytokines and cells with 
genomic arrays for molecular networks or pathways; transbronchial lung biopsy 
tissue can be used as possible for similar genomic mapping studies
o assess alveolar macrophages and dendritic cells for innate immune activity 
and cellular receptors
o from mediastinal lymph node biopsy tissue and use of laser capture 
microdisection, isolate immune cells for genomic and proteomic studies 

This RFA will use the National Institutes of Health (NIH) Research Project 
Grants (R21) award mechanism(s).  The R21 is intended to encourage exploratory 
and developmental research projects by providing support for the early and 
conceptual stages of these projects.  The characteristics, requirements, 
preparation, and review criteria for the R21 application are described. 
Information on the R21 award mechanism can be found at

This mechanism does not require preliminary data but emphasizes creative and 
innovative approaches. The total project period for an application submitted in 
response to this RFA may not exceed 2 years.  The maximum funds (direct costs) 
available over a 2 year period of support is $275,000.  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 should be submitted 
as regular research (R01) grants that 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, 2004.  Applications 
that are not funded in the competition described in this RFA may be resubmitted 
as NEW investigator-initiated R01 applications using the standard receipt dates 
for NEW applications described in the instructions to the PHS 398 application.  

This RFA uses just-in-time concepts.  It also uses the modular budgeting format. 
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular format.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at  

The NHLBI intends to commit approximately $4,500,000 in FY 2004 to fund up to 
10 new grants in response to this RFA. An applicant may request a project 
period of up to 2 years and a budget for direct costs of up to $275,000 for the 
2 year period (but no more than $200,000 in any one year). 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.  
You may submit (an) application(s) if your institution has any of the following 
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


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.   

Applications must propose research projects that focus on sarcoidosis and/or on 
lung granulomatous inflammation that is relevant to sarcoidosis.  Basic 
immunologic studies not related to granulomatous lung inflammation are not 
responsive to this RFA.  Also, projects related to hypersensitivity pneumonitis 
from organic antigens, beryllium exposure or eosinophilic granuloma are not 
considered responsive to this RFA, nor are projects involving Mycobacterium 

Grantee's 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 
in about 6 months after the award is issued.

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 sarcoidosis 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 and address how this information will be included as part of the 
patient consent process.  Such sharing of tissue will also facilitate 
identification and evaluation of different potential targets in the same 
tissue from the same patient.  

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 

o Direct your questions about scientific/research issues to:

Herbert Y. Reynolds, M.D.
Medical Officer, Lung Biology and Disease 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

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 7214, MSC 7924
Bethesda, MD  20892-7924 (20817 for express/courier service)
Telephone:  (301) 435-0270
FAX:  (301) 480-0730

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

Robert Pike
Grants Management Officer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7144, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310

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, 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 Dr. Anne Clark at the address 


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive format.  
For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
SUPPLEMENTAL INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001) must 
be followed, with these exceptions:

o Research Plan

Items a-d of the Research Plan (Specific Aims, Background and Significance, 
Preliminary Studies, and Research Design and Methods) may not exceed a total of 
15 pages.  No preliminary data are required but may be included if available.  
Please note that a Progress Report is not needed; competing continuation 
applications for an exploratory/developmental grant will not be accepted.

Appendix.  Use the instructions for the appendix detailed in the PHS 398 except 
that no more than 5 manuscripts, previously accepted for publication, may be 

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:
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, plus all 
collated sets of appendix material must be sent to Dr. Anne Clark at the address 
listed under where to send inquires.

APPLICATION PROCESSING: Applications must be received on or before 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 

Although there is no immediate acknowledgement of the receipt of an application, 
applicants are generally notified of the review and funding assignment within 8 
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.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes.  While the 
investigator may still benefit from the previous review, the RFA application is 
not to state explicitly how.

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness to special requirements of the RFA by the NHLBI.  Incomplete 
and/or non-responsive applications will be returned to the applicant without 
further consideration.

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 NHLBI 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 Advisory 

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: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria in 
assigning the application's overall score, weighting them as appropriate for 
each application.  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 

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?

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?

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

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

subjects and protections from research risk relating to their participation in 
the proposed research will be assessed. (See criteria included in the section 
on Federal Citations, below).
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 in the sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be 
used in the project, the five items described under Section f of the PHS 398 
research grant application instructions (rev. 5/2001) will be assessed.  


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

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


Letter of Intent Receipt Date:  September 22, 2003
Application Receipt Date:  October 20, 2003
Peer Review Date:  February - March 2004
Council Review:  May 13, 2004
Earliest Anticipated Start Date:  July 1, 2004


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.

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and others, 
and the importance of the knowledge gained or to be gained. 

involving Phase I and II clinical trials must include provisions for assessment 
of patient eligibility and status, rigorous data management, quality assurance, 
and auditing procedures.  In addition, it is NIH policy that all clinical trials 
require data and safety monitoring, with the method and degree of monitoring 
being commensurate with the risks (NIH Policy for Data and Safety Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998:  

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 "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 
a complete copy of the updated Guidelines are available at
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.

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

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

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at and at  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding 
(see   It is the responsibility of the applicant 
to provide, in the project description and elsewhere in the application as 
appropriate, 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.

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

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.

Department of Health and Human Services (DHHS) issued final modification to the 
"Standards for Privacy of Individually Identifiable Health Information", the 
"Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal regulation 
under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 
that governs the protection of individually identifiable health information, 
and is administered and enforced by the DHHS Office for Civil Rights (OCR). 
Those who must comply with the Privacy Rule (classified under the Rule as 
"covered entities") must do so by April 14, 2003  (with the exception of small 
health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
( provides information on the 
Privacy Rule, including a complete Regulation Text and a set of decision tools 
on "Am I a covered entity?"  Information on the impact of the HIPAA Privacy 
Rule on NIH processes involving the review, funding, and progress monitoring 
of grants, cooperative agreements, and research contracts can be found at

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

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance at and is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 
and 284 and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 

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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