MOLECULAR MECHANISMS OF MUCOUS CELL METAPLASIA AND EXCESS MUCOUS SECRETION IN 
HUMAN AIRWAY DISEASES

Release Date:  December 13, 2001

RFA:  RFA-HL-02-011

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

Letter of Intent Receipt Date:  May 17, 2002
Application Receipt Date:       June 14, 2002

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN 
$250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN 
SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The intent of this solicitation is to promote research on the molecular and 
cellular mechanisms involved in hypersecretion of mucus and mucous cell 
metaplasia in human airway diseases.

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 Request for Applications (RFA), 
Molecular Mechanisms of Mucous Cell Metaplasia and Excess Mucous Secretion In 
Airway Diseases, 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) 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 April 1, 2003.

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).  

FUNDS AVAILABLE

The National Heart, Lung, and Blood Institute (NHLBI) intends to commit 
approximately $3,750,000 in FY 2003 to fund approximately ten new and/or 
competitive continuation 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 10 modules at $25,000 per module ($250,000 direct costs) 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

Mucous cell metaplasia with mucous hypersecretion is a prominent manifestation 
of many common inflammatory diseases of the upper and lower airways.  Excess 
production of mucus is a problem in both minor and serious illnesses, ranging 
from the common cold to fatal exacerbations of chronic bronchitis, asthma, and 
cystic fibrosis.  Control of mucous hypersecretion is a difficult challenge 
because of the complex roles of mucus in host defenses, the variety of stimuli 
that can induce mucous secretions, the redundancy of the signal transduction 
pathways involved, and the multiplicity of mucin genes.  Available treatments 
for airway diseases, including anti-inflammatory drugs, antibiotics, and 
bronchodilators, are generally ineffective for suppression of mucous 
secretions.  Knowledge of the molecular pathways that regulate secretion and 
metaplasia in the pulmonary mucous cells of individuals with airway diseases 
might aid the rational development of new drugs for the control of mucous 
function.

While the physiological consequences of mucous production are well understood, 
little is known regarding the specific molecular pathways involved in 
regulation of mucous secretions in airway diseases.  For example, in chronic 
obstructive pulmonary disease (COPD), it is not known which mucins are 
secreted in excess, which pathways regulate their secretion, or how these 
pathways are dysfunctional in disease.  The relative importance of cellular 
stimulation and of cellular metaplastic transformation is poorly understood, 
and differential regulation of epithelial goblet cells and submucosal glands 
has not been adequately examined.  Mechanisms for acute and chronic regulation 
of mucous secretion have not been distinguished.  Possible differences in 
mucous pathways between smokers with and without chronic bronchitis have not 
been investigated in detail.  Finally, it is not known if the alterations in 
mucous function in COPD reflect irreversible changes in the mucous cells 
themselves or if exuberant mucus is due to an ongoing physiological response 
to a potentially interruptible stimulus.  There are similar gaps in knowledge 
regarding mucous function in other airway diseases.

Recent research advances offer new opportunities for progress in studies of 
airway mucous function.  These advances include identification of signal 
transduction pathways involved in the regulation of mucin secretion, cloning 
of multiple mucin genes, development of molecular probes for studies of mucin 
gene expression, and methodological improvements for molecular histopathology. 
 There has been fundamental progress in the cell biology of protein processing 
and of cellular phenotypic transformations.  Structure/function relationships 
in glycoproteins have been shown, and powerful experimental tools for 
glycobiology have been developed.  Finally, with refinement of methods for the 
production of transgenic mice, studies to address the pathophysiological roles 
of specific proteins or pathways are increasingly feasible.  Application of 
this knowledge and these techniques offers great promise for research to 
define "healthy" mucous function, characterize mucous abnormalities in airway 
diseases, elucidate differences in pathogenesis among various airway diseases, 
and identify therapeutic targets for modulation of mucous function.

Other

This RFA solicits applications for research to delineate the molecular and 
cellular mechanisms of mucous hypersecretion and mucous cell metaplasia in 
humans with chronic airway diseases such as COPD, asthma, cystic fibrosis, and 
other chronic bronchitic conditions.  Studies may consider several airway 
conditions or focus on one particular disease.  Applications should be 
hypothesis-driven and should address molecular and/or cellular aspects of 
mucous function, with emphasis on the chronic regulation of mucous secretion 
and mucous cell metaplasia.  The proposed research must seek new knowledge 
that leads toward the eventual development of therapeutic agents for the 
clinical modulation of mucous function in human airway diseases.

Applications responding to this RFA must include studies of specimens 
(tissues, cells, fluids, etc.) from human subjects with chronic airway 
disease(s).  These experiments may be integrated with basic science studies 
that employ animals or in vitro model systems.  For example, molecular studies 
of specific mucous pathways in animal models or in primary cultures of normal 
airway epithelial cells might be combined with measurements that assess the 
presence and operation of these pathways in the airway mucous cells of humans 
with and without airway disease.  Collaborative applications involving basic 
and clinical scientists are encouraged.

A broad range of topics related to the molecular and cellular mechanisms 
involved in mucous function may be considered including, but not limited to, 
the expression and localization of specific mucin mRNAs and proteins, the 
constituents and activities of particular mucous regulatory pathways, and the 
character and extent of mucous metaplasia at different airway levels in humans 
with airway diseases.  Studies might address regulation of mucin gene 
expression, mechanisms for the transcription, synthesis, and secretion of 
specific mucins, signal transduction pathways involved in enhancement of 
mucous secretion or in cellular metaplastic transformation, responsiveness of 
mucous regulatory pathways to microbial, inflammatory, and proteolytic 
stimuli, or strategies for preventing hypersecretion of mucins.  Relevant 
questions might include, but are not limited to, the following:

o  What mucins are synthesized and secreted by specific cell types at 
different levels in the airway tree in health and in particular diseases?
o  What pathways regulate the expression of mucin gene products in the 
airways, and how are these pathways altered in disease?
o  What pathways regulate the differentiation and metaplastic transformation 
of goblet and glandular mucous cells in the airways, and how are these 
pathways activated in disease?
o  What are the time course and the capacity for reversibility of cellular and 
molecular changes associated with mucous metaplastic transformation?
o  How are the pathways that govern mucous function in the airways affected by 
mediators associated with chronic airway diseases (e.g., neurotransmitters, 
reactive oxidant species, cytokines, and proteases)?
o  Are particular pharmacological agents effective in preventing or reversing 
experimentally-induced mucous metaplasia and mucous hypersecretion?

SPECIAL REQUIREMENTS

Relevance of the proposed work to human airway disease and involvement of 
human subjects with airway disease are important requirements of this RFA.    
Applications that do not involve studies of humans subjects or materials 
derived from human subjects (e.g., tissues, cells, or fluids) will be 
considered non-responsive.  However, the emphasis of this RFA is on the 
molecular and cellular mechanisms that regulate airway mucous function and not 
on the clinical consequences of excess mucous secretion.  Applications that do 
not address molecular or cellular aspects of airway mucous function will be 
considered non-responsive to the RFA.  Descriptive or technical aims (e.g., 
development of minimally invasive methods for quantifying and characterizing 
airway mucous secretions in humans) may be included.  Nonetheless, wholly 
descriptive or technical studies that do not address mechanistic hypotheses 
will be considered non-responsive.

Relevance to human airway disease should guide the choice of any experimental 
model system.  Since in vitro systems may differ substantially from mucous 
cells in vivo, applicants should describe any methods for culture of primary 
cells or tissue explants and indicate what control measurements will be used 
to characterize the state of mucous differentiation of these cells.  
Applications for studies of cell lines are generally discouraged, although 
cell lines may be appropriate to certain research questions.  Applicants 
should justify their use of a cell line, should such a model be scientifically 
advisable.  Relevance to human disease should also influence the nature of any 
challenges that are employed in the studies.  For example, effects of chronic 
exposures to inflammatory mediators on mucous pathways may be more relevant to 
human disease than would be the acute effects of an irritant gas.

It is understood that mucous secretion and metaplasia in the nose or sinuses 
might be reflective of mucous behavior in the more caudal airways.  
Nonetheless, all research programs supported by this RFA must include studies 
that are anatomically related to the trachea or intrathoracic conducting 
airways.  This requirement is not intended to exclude studies that might 
contrast mucous pathways in the upper and lower airways.

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 one-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 may contact the program official 
listing 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 clinical research 
projects unless a clear and compelling justification is provided indicating 
that inclusion is inappropriate with respect to the health of the subjects or 
the purpose of the research. This policy results from the NIH Revitalization 
Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.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

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 
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.

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.

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.

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 Chief, Review Branch, at the address 
listed under INQUIRIES by May 17, 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 must be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable format. For further assistance contact GrantsInfo, 
Telephone 301/710-0267, Email:  [email protected].

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 provided in 
Section C of the application instructions.

The RFA label available in the PHS 398 (rev. 5/2001) application form or at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf 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.

Submit a signed, typewritten original of the application, including the 
Checklist, and three photocopies of the original with signatures 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 Chief, Review 
Branch, 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 any 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 Chief, Review 
Branch, 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 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 
methods? 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 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:    May 17, 2002
Application Receipt Date:         June 14, 2002
Peer Review Date:                 October-November 2002
Council Review:                   February 6-7, 2003
Earliest Anticipated Start Date:  April 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.

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:  [email protected]

Send letter of intent, two copies of the application, and direct inquiries 
regarding review issues to:

Chief, Review Branch
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:  [email protected]

Direct inquiries regarding fiscal matters to:

Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7158, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  [email protected]

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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