INFLAMMATION IN THE PATHOGENESIS OF COPD

Release Date:  November 2, 1999

RFA: HL-00-006

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date: February 1, 2000
Application Receipt Date: March 10, 2000

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

PURPOSE 
 
The National Heart, Lung, and Blood Institute (NHLBI) invites research grant 
applications to conduct studies on the role of inflammation in the pathogenesis 
of chronic obstructive pulmonary disease (COPD). The overall goal of this 
program is to establish the cellular and molecular mechanisms of inflammatory 
and immune processes which play a role in the pathogenesis and progression of 
COPD.  Toward this goal, this initiative strongly encourages scientific 
collaborations among investigators with interest in COPD, inflammation and 
immunology. 

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 Request for Applications (RFA), 
"Inflammation in the Pathogenesis of COPD", 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 or local governments, and eligible agencies of the 
Federal government.  Awards under this RFA to foreign institutions will be made 
only for research of very unusual merit, need, and promise, and in accordance 
with PHS policy governing such awards.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This RFA 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 RFA may 
not exceed 4 years.  This RFA is a one-time solicitation.  Future unsolicited 
competing continuation applications will compete with all investigator-initiated 
applications and be reviewed according to the customary peer review procedures.  
The anticipated award date is September 29, 2000.

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. 

Applicants from institutions that have a General Clinical Research Center (GCRC) 
funded by the NIH National Center for Research Resources may wish to identify 
the GCRC as a resource for conducting the proposed research.  If so, a letter of 
agreement either from the GCRC program director or principal investigator should 
be included with the application.

FUNDS AVAILABLE

The NHLBI intends to commit approximately $3,200,000 total costs in fiscal year 
2000 to fund 6 to 8 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 of up to 
$225,000 per year, including facilities and administrative costs (F&A) on 
consortium arrangements. The total cost for a consortium arrangement is included 
in the overall requested modular direct cost amount.  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 National Heart, Lung 
and Blood Institute 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 applications of strong scientific and technical merit. 

RESEARCH OBJECTIVES 

Background

Chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis 
and emphysema, is characterized by chronic and progressive airflow limitation.  
It affects more than 16 million Americans, is the fourth leading cause of death 
in the USA, and costs the nation billions of dollars for direct and indirect 
health care.  Although cigarette smoking has been recognized as a major causal 
factor in the majority of cases, it remains a major societal issue and both 
mortality and prevalence rates of COPD are continuing to rise.

COPD is most likely a complex of conditions with multiple initiating and 
effector pathways.  Research in COPD has primarily focused on the role of 
proteases and antiproteases in the generation of emphysema, a subset of COPD.  
Although inflammation has always been considered a prominent feature in COPD, 
there has been little work describing the specific inflammatory and immune 
events in COPD and their role in the pathogenesis of disease.   Recently, 
several studies have shown steroids, so effective in treatment of asthma, to be 
of limited therapeutic value in COPD.  This has underscored the need to 
characterize and elucidate the inflammatory pathways in COPD. This includes 
initiating events, regulatory mechanisms and subsequent underlying cellular and 
molecular processes which lead to inflammation, tissue damage and remodeling.  
These insights should lead to a better understanding of the pathogenic 
mechanisms of COPD and provide a basis for the development of therapeutic 
modalities specific to COPD as distinguished from other obstructive pulmonary 
diseases.

Other

Preliminary descriptions report that the lymphocytic infiltrate in COPD appears 
to vary with specific syndrome, severity and stability versus exacerbation.  
Furthermore, while most smokers will have some degree of inflammation in their 
airways, only about 15 percent will go on to develop the clinical syndrome of 
COPD.  Rigorous identification, at the cellular and molecular level, of the 
various inflammatory and immune pathways present in COPD and how they may 
differ from smokers who do not get disease is an important goal in understanding 
pathogenesis at the mechanistic level.  While cigarette smoke or other 
environmental stimuli are thought to be the primary initiators of the 
inflammatory response, the mechanisms involved and other co-initiators have not 
been identified.  It is possible that smokers exist in a heightened local 
inflammatory state that, in some, leads to long term damage and remodeling of 
the airways that may be further exacerbated by infection or other events.  
Proinflammatory molecules such as endotoxin and lipopolysaccharide (LPS), as 
well as the adenovirus protein E1A, are known to play a role in the upregulation 
of inflammation.  Specific cells and factors, such as cytokines, chemokines, 
along with initiating events, regulatory mechanisms, need to be identified and 
characterized to determine their role in COPD.  Cellular migration, infiltration 
and activation state also need to be investigated.  It is also necessary to 
determine the potential influence of the involved pathways and their components 
on resident airway cell function and extracellular matrix (ECM). Inflammatory 
cytokines and cells may be involved in goblet cell hyperplasia and the 
appearance and increase of goblet cells in the small airways.  This relationship 
needs to be investigated and defined.  Elucidation of these molecular events is 
critical to defining the mechanisms which underlie development and progression 
of COPD.

Additionally, the relationships among inflammation, cell activation and cell-
cell and cell-matrix interactions as they relate to altered  airway function in 
COPD are poorly understood and require further study.  The role of inflammatory 
cells and cytokines as they relate to the structural integrity of the airways 
needs to be investigated.  For example, enzymes which play a role in the 
activation of matrix metalloproteinases (MMPs) have been identified, and are 
known to be upregulated, in alveolar macrophages from COPD patients.  Cellular 
events that are required for increased expression and activation of these 
enzymes need to be identified.  ECM fragments have been demonstrated to be 
chemotactic for inflammatory cells and contact with disrupted ECM is known to 
activate multiple signaling pathways triggering many cellular responses.  It 
will be important to determine the relationship between inflammation, MMP 
activation and ECM degradation and also to further investigate the potential 
role of MMPs and ECM fragmentation in remodeling of the airways and perpetuation 
of the inflammatory process.

THESE ARE EXAMPLES ONLY.  INVESTIGATORS SHOULD NOT FEEL LIMITED TO THE EXAMPLES
MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE 
OBJECTIVES OF THE RFA.

SPECIAL REQUIREMENTS

Applications that propose descriptive studies and do not contain hypothesis 
driven studies directed at understanding the mechanisms associated with 
inflammatory and immune events and their relationship with the pathogenesis of 
COPD will not be responsive to the RFA.  The intent of this initiative is to 
focus on the pathogenesis of COPD.  Applications using in vitro, cellular, 
or animal models, including humans, to study inflammatory mechanisms as they 
relate to COPD will be considered responsive.  Applicants who propose to test 
hypotheses in animal or in vitro models must demonstrate relevance to 
inflammation and/or immunology and its relationship with COPD pathogenesis 
and/or disease progression.  Studies directed solely at inflammatory and/or 
immune  events, without relevance to COPD, will not be responsive to this 
initiative.  Multidisciplinary investigations bringing together investigators 
with expertise in COPD, immunology, inflammation and molecular and cellular 
biology are strongly encouraged.  Large clinical studies or epidemiologic 
studies are not within the scope of this RFA. 

Upon initiation of the program, the NHLBI will sponsor periodic meetings to 
encourage exchange of information among investigators who participate in this 
program.  Travel funds for a one day meeting each year, most likely to be held 
in Bethesda, Maryland, should be included in the modules.  Applicants should 
also include a statement in their application indicating their willingness to 
participate in these meetings and to interact openly with other study 
participants so as to provide the greatest promise for scientific advances from 
the approved research scope of the awards.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their 
subpopulations must be included in all NIH supported biomedical and  behavioral 
research projects involving human subjects, unless a clear and compelling 
rationale and justification is provided that inclusion is inappropriate with 
respect to the health of the subjects or the purpose of the research.  This new 
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public 
Law 103-43).

All investigators proposing research involving human subjects should follow 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, Volume 23, 
Number 11, March 18, 1994, available on the web at:
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 the 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.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel and 
participating institutions, and the number and title of the RFA in response to 
which the application may be submitted.  Although a letter of intent is not 
required, is not binding, and does not enter into the review of subsequent 
applications, the information that it contains allows NHLBI staff to estimate 
the potential review workload and to avoid conflict of interest in the review.

The letter of intent is to be faxed or mailed to Dr. C. James Scheirer as the 
address listed under INQUIRIES.

APPLICATION PROCEDURES

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 the applicant 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 
maximum total direct cost request of $225,000 per year.  An R01 grant 
application may include research activities that involve institutions other than 
the sponsoring organization, creating a consortium effort.  The consortium costs 
should be included in the direct cost limit ($225,000).  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:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $225,000) and Total Costs [Modular Total 
Direct plus 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-DD of the PHS 398 (rev 4/98).  It is not required nor will it be accepted at 
the time of 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.  For this RFA, the consortium costs should be included in the $225,000 
cost limit.  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 collaborative 
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 modified 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 citation;

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 research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and 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.

The RFA label found in the PHS 398 (rev. 4/98) application form must be affixed 
to the bottom of the face page of the application.  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 
(Inflammation in the Pathogenesis of COPD) and number (HL-00-006) must be 
typed on line 2 of the face page of the application form and the YES box must be 
marked.  Please be sure to include the RFA number (HL-00-006) on the label.

The sample RFA label available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

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 must be sent 
to Dr. C. James Scheirer, at the listing under INQUIRIES.

APPLICATIONS MUST BE RECEIVED BY MARCH 10, 2000.  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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by 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, a process will be used by the initial review group in 
which applications 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 the applications under review, will be discussed, assigned a 
priority score, and receive a second level review by the National Heart, Lung, 
and Blood 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 
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 the assigning the overall score, 
weighing them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged 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 the research 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 that may be adversely affected by the project 
proposed in the application.

The personnel category will be reviewed for appropriate staffing based on the 
requested percent effort and justification provided.  The direct costs budget 
request will be reviewed for consistency with the proposed methods and specific 
aims.  Any budgetary adjustments recommended by the reviewers will be in $25,000 
modules.  The duration of support will be reviewed to determine if it is 
appropriate to ensure successful completion of the requested scope 
of the project.

Schedule

Letter of Intent Receipt Date:     February 1, 2000
Application Receipt Date:          March 10, 2000
Date of Initial Review:            May/June 2000
Review by NHLBI Advisory Council:  September 7-8, 2000 
Anticipated Award Date:            September 2000

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 and program balance

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Patricia Noel, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room10018, MSC 7952
Bethesda, Maryland 20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
Email: noelp@nih.gov

or

Gail Weinmann, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room10018, MSC 7952
Bethesda, Maryland 20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
E-mail: weinmang@nih.gov

Direct inquiries regarding review matters and address the letter of intent to:

C. James Schreirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, Maryland 20892-7924
Telephone: (301) 435-0266
FAX: (301) 480-3541
E-mail: JS110J@nih.gov

Direct inquiries regarding fiscal matters to:

Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154, MSC 7926
Bethesda, MD 20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
E-mail: 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, amended by Public Law 99-158, 42 USC 241 
and 285) and administered under PHS grants policies and Federal Regulations 42 
CFR 52 and 45 CFR Part 74.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or a Health Systems Agency Review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  In addition, Public 
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care or early childhood development 
services are provided to children.  This is consistent with the PHS mission to 
protect and advance the physical and mental health of the American people.


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