NOVEL BIOMARKERS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Release Date:  July 24, 2001

RFA:  RFA-HL-02-005

National Heart, Lung, and Blood Institute
 (http://www.nhlbi.nih.gov)

Letter of Intent Receipt Date:  January 25, 2002
Application Receipt Date:       February 26, 2002

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites applications for 
research grants to identify novel biomarkers of chronic obstructive pulmonary 
disease (COPD).  COPD is a complex group of conditions associated with 
progressive airway obstruction for which no disease-modifying therapy is 
currently known.  The purpose of this Request for Applications (RFA) is to 
promote the identification and characterization of biomarkers that might 
eventually be useful for studies of COPD pathogenesis, for diagnosis, for 
therapeutic stratification of patients, or for testing of potential drug 
treatments.  Such biomarkers might reflect the presence or severity of COPD, 
the rate of disease progression, or exacerbations of the disease.  A variety 
of techniques might be employed, ranging from chemical assays of exhaled air 
condensate to proteomic analysis of blood to functional imaging of lungs by 
positron emission tomography (PET).  The focus of this RFA is on novel 
biomarkers for COPD that can be determined by minimally invasive means.

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, Novel Biomarkers of Chronic 
Obstructive Pulmonary Disease (COPD), 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/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Research Project 
(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 four 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 30, 2002.


Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

The NHLBI intends to commit approximately $3.5 million in FY 2002 to fund 
eight to ten new grants in response to this RFA. An applicant may request a 
project period of up to four years and a budget for direct costs of up to 
$350,000 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. At this time, it 
is not known if this RFA will be reissued.

RESEARCH OBJECTIVES

Background

COPD is a progressive disease, usually related to cigarette smoking, that 
affects 15 million Americans and is the fourth leading cause of death in this 
country.  Attempts to reduce rates of smoking have been only minimally 
successful and COPD will likely be an increasingly important cause of 
disability and premature death in the future.  There is remarkable 
heterogeneity among affected individuals with regard to the severity, rate of 
progression, and clinical manifestations of their disease.  There is currently 
no reliable way to predict which individuals will develop COPD or which 
patients with COPD will experience rapid loss of lung function.  Improvements 
are needed in our understanding of the disease process and in methods for 
characterizing subjects with this disease.  Identification of biomarkers could 
lead to better understanding of the mechanisms of COPD and could facilitate 
the development of innovative therapies.

Previous studies of chemical biomarkers in COPD, while typically involving 
only a small number of subjects, have yielded several encouraging findings.  
Individuals with stable COPD had increased markers of oxidative stress in 
exhaled air and plasma, increased levels of myeloperoxidase and eosinophil 
cationic protein in serum, and increased levels of eosinophil peroxidase and 
human neutrophil lipocalin in sputum.  Urinary concentrations of desmosine and 
isodesmosine, degradation products of elastin, were correlated with both the 
presence of COPD and with disease exacerbation.  Various inflammatory 
mediators and products of inflammatory cells were increased in serum during 
periods of exacerbation of COPD.  Microsatellite DNA instability was detected 
in sputum cells of one fourth of smokers with severe COPD but in none of 
smokers without COPD.  Validation and extension of these findings is needed in 
larger groups of subjects with COPD that are stratified by disease expression 
and severity.

There has been little use of advanced techniques in studies of potential 
biomarkers for COPD.  In one preliminary report involving measurements by 
positron emission tomography, activation of neutrophils and uptake of 
macrophages were greater in the lungs of subjects with COPD than in normal 
controls.  No studies involving proteomic analysis or gene expression 
profiling by microarray analysis have been reported.

Other


This RFA invites studies to examine associations between specific aspects of 
COPD and novel biomarkers that are measured by minimally invasive methods.  A 
biomarker is defined in the RFA as a physiological or anatomical measurement 
or the quantitative result of a physical, chemical, or cellular analysis of a 
biological specimen obtained from a human subject.  This definition includes, 
but is not limited to, the following:

o Measurements of chemicals or biochemicals in biological fluids,
o Quantitation of specific cell types by histological or chemical 
characteristics,
o Proteomic analysis,
o Gene expression profiles,
o Innovative physiological measures such as airway impedance,
o High resolution computed tomography, and
o Functional imaging technologies such as positron emission tomography (PET).

A biomarker to be evaluated through this RFA must be novel, i.e. it must 
reasonably be expected to capture information about the disease state that is 
substantially different from or substantially more detailed than that which 
can be obtained through established methods for characterizing subjects with 
COPD.  These established methods include spirometry, measurements of gas 
diffusing capacities, and radiographic measures of lung tissue density.

A biomarker to be evaluated through this RFA must involve only minimally 
invasive methods for measurements or sample collection.  Examples of minimally 
invasive techniques are sampling of exhaled air, sputum induction, peripheral 
venous blood draws, urine collection, plethysmography, and use of radiographic 
imaging methods.

Proposed studies must involve characterizations of human subjects and must 
include individuals who have COPD.  Studies of individuals with alpha-1 
antitrypsin deficiency will be allowed.  It is expected that studies will 
attempt to correlate particular biomarkers with specific aspects of COPD.  
Examples of aspects of COPD include, but are not limited to:

o Presence or absence of stable COPD in smokers,
o Degree of airflow limitation,
o Symptoms of chronic bronchitis,
o Severity and/or distribution of emphysema,
o Responsiveness to therapies for COPD,
o Frequency of exacerbations, or
o Disease exacerbation.

Measurements of multiple biomarkers in individual subjects and testing of 
multivariate correlations are encouraged.  However, applicants should explain 
their rationale for the choice of each putative biomarker, should clearly 
define the aspect of COPD that is hypothesized to be correlated with the 
biomarker, and should justify the selection of the group(s) of human subjects 
that will be studied in the context of the underlying hypothesis.  Examples of 
possible comparisons, depending upon the biomarker and the hypothesis, 
include:

o Between smokers with and without COPD,
o Between current smokers and non-smokers with COPD, 
o Between members of a single group of COPD subjects with varying rates of 
decline in FEV1 over time,
o Between subjects with COPD and subjects with asthma, and
o Between samples obtained in a single group of subjects during stable COPD 
and during exacerbations.


Other comparisons not listed may also be appropriate.  Plans for subject 
recruitment and characterization should be described in detail.  The use of 
previously characterized cohorts of subjects is encouraged, particularly for 
studies attempting to correlate biomarkers with the rate of disease 
progression.

SPECIAL REQUIREMENTS

Studies of animals and in vitro models will not be funded through this RFA.

Studies supported through this RFA must not employ invasive methods for the 
collection of specimens to be assayed for biomarkers.  Proposals involving 
biomarkers in bronchoalveolar lavage fluid, in biopsies, or in surgical 
specimens will be judged as nonresponsive and returned to the applicant 
without scientific review.

Applications to study physiological measurements or x-ray images will be 
considered responsive to the RFA only if the proposed measurements are likely 
to yield information that is substantially different from that which can be 
obtained by standard methods of pulmonary function testing and computed 
tomography (CT).  This restriction does not preclude comparisons of standard 
measures (e.g. spirometry, lung CT) to the proposed novel biomarkers.  In 
fact, measurements using established methods will generally be necessary for 
the characterization of the research subjects.

It is recognized that certain characterizations of human subjects that might 
be obtained through this RFA could also serve as phenotypes in studies testing 
associations of candidate gene polymorphisms with COPD.  While it is not the 
intent of this RFA to support genetic studies, funds may be requested for the 
collection and storage of DNA specimens.  Funds will not be provided for 
genotyping of study participants.  Any applicant wishing to make use of this 
option must describe briefly the planned use of study data and DNA specimens, 
must specify what costs for DNA collection and storage are included in the 
proposed budget, and must obtain Institutional Review Board approval for the 
collection and storage of these biological specimens.

Upon initiation of the program, periodic meetings will be organized to 
encourage the exchange of information among investigators who participate in 
this program.  Travel funds for a two day meeting each year, most likely to be 
held in Bethesda, Maryland, must be included in the module calculation.  
Applicants must include a statement indicating their willingness to 
participate in these meetings.  Applicants are encouraged to contact the 
program official listed under INQUIRIES for further information.

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 sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, of sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL: 
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.

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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

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.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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 RFA 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.

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 
a subsequent application, the information that it contains allows NHLBI staff 
to estimate the potential review workload and plan the review.

The letter of intent is to be sent to Dr. Deborah Beebe at the address listed 
under INQUIRIES by January 25, 2002.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format. Although applicants are strongly 
encouraged to begin using the 5/2001 revision of the PHS 398 as soon as 
possible, the NIH will continue to accept applications prepared using the 
4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, 
the NIH will return applications that are not submitted on the 5/2001 version. 
 For further assistance contact GrantsInfo, Telephone 301/435-0714, Email: 
GrantsInfo@nih.gov.

It is expected that most grant applications submitted in response to this RFA 
will request no more than $250,000 direct costs in any year.  Such 
applications must use a Modular Budget Format.  Applications involving 
exceptional costs such as those associated with characterization of a large 
number of research subjects or use of advanced technologies may request up to 
$350,000 direct costs per year.  Applications requesting greater than $250,000 
direct costs in any year are required to include a categorical budget request 
using Form Page 4 and Form Page 5 of the PHS 398 (rev. 05/01).

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and NIH staff. 
 The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions beginning on page 
13 of the application instructions.

SUBMITTING YOUR APPLICATION

The RFA label available in the PHS 398 (rev. 05/01) 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 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 as well as 
all five collated sets of Appendix material must be sent to Dr. Deborah Beebe 
at the address listed under Inquiries.

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 yet received such a letter, contact Dr. Deborah 
Beebe at the address listed under Inquiries.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness 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 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 NHLBI 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 the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.


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

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

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

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

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

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

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

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

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

Schedule

Letter of Intent Receipt Date:    January 25, 2002
Application Receipt Date:         February 26, 2002
Peer Review Date:                 June/July, 2002
Council Review:                   September 5-6, 2002
Earliest Anticipated Start Date:  September 30, 2002

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.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Tom Croxton, Ph.D., M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10208, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
Email:  croxtont@nhlbi.nih.gov

Direct inquiries regarding review issues to:

Deborah Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, MD  20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-3541
Email: beebed@nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Marsha Mathis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7158, MSC 7926
Bethesda, MD  20892-7926
Telephone: (301) 435-0170
FAX:  (301) 480-3510
Email:  mathism@nhlbi.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 Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant 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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