Full Text HL-94-008

SPECIALIZED CENTERS OF RESEARCH IN PATHOBIOLOGY OF FIBROTIC LUNG
DISEASE, PATHOBIOLOGY OF LUNG DEVELOPMENT, AND CELLULAR AND MOLECULAR
MECHANISMS OF ASTHMA

NIH GUIDE, Volume 23, Number 20, May 27, 1994

RFA:  HL-94-008

P.T. 04

Keywords: 
  Asthma 
  Pulmonary Diseases 
  Biology, Molecular 
  Pathophysiology 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  December 15, 1994
Application Receipt Date:  July 14, 1995

PURPOSE

The primary objective of the Specialized Centers of Research (SCORs)
programs supported by the Division of Lung Diseases is to foster
multidisciplinary basic and clinical research enabling basic science
findings to be more rapidly applied to clinical problems.  The basic
and clinical research to be supported through this RFA will be
related to one of the above three categories.  It is expected that
results from these SCOR grants will have an impact on the prevention,
diagnosis, and treatment of fibrotic lung disease, pulmonary diseases
in infants and children, and asthma.

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), SCORs in Pathobiology of Fibrotic Lung
Disease, Pathobiology of Lung Development, and Cellular and Molecular
Mechanisms of Asthma, is related to the priority areas of
occupational safety and health, environmental health, maternal and
infant health, diabetes and chronic disabling diseases and
immunization and infectious diseases.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit domestic
institutions, public and private, such as universities, colleges,
hospitals, and laboratories.  This RFA is intended to support SCOR
grants for basic and clinical investigations.  Applications that
include only basic or only clinical research will not be responsive.
In addition, clinical research projects focused on large
epidemiologic studies or large clinical trials will be considered
unresponsive to this RFA.  Awards will not be made to foreign
institutions.  However, under exceptional circumstances, a foreign
component critical to a project may be included as a part of that
project.  Women and minority investigators are encouraged to apply.

The Principal Investigator should be an established research
scientist with the ability to ensure quality control and the
experience to administer effectively and integrate all components of
the program.  A minimum time commitment of 25 percent is expected for
this individual.  The Principal Investigator must also be the project
leader of one of the component research projects.  If, through peer
review, this project is not recommended for further consideration,
the overall SCOR application will not be considered further.  If this
project  is judged by peer review to be of low scientific merit, it
will markedly reduce the overall scientific merit ranking assigned to
the entire application by the review committee.  Project leaders must
agree to commit at least 20 percent effort to each project for which
they are responsible.

MECHANISM OF SUPPORT

This RFA will use the National Heart, Lung, and Blood Institute
(NHLBI) SCOR (P50) grant to support this research program.  All
applications received in response to this solicitation will be
considered as new applications.  Applications submitted by current
SCOR groups must be sufficiently changed to meet the objectives of
one of the three programs described in this RFA.  Responsibility for
the planning, direction, and execution of the proposed project will
be solely that of the applicant.  All current policies and
requirements that govern the research grant programs of the NIH will
apply to grants awarded under the RFA.

Basic and Clinical Research

The overall concept of a SCOR program focuses on scientific issues
related to diseases relevant to the mission of the NHLBI.  It is
essential, therefore, that all applications include both basic and
clinical research projects.  Interactions between basic and clinical
scientists are expected to strengthen the research, enhance transfer
of fundamental research findings to the clinical setting, and
identify new research directions.  Plans for transfer of findings
from basic to clinical studies should be described.

Each SCOR grant application and award must include research involving
human patients/subjects.  Support may be provided for human
biomedical and behavioral studies of etiology, pathogenesis,
prevention and prevention strategies, diagnostic approaches, and
treatment of diseases, disorders or conditions.  Small
population-based studies, where the research can be completed within
five years, may also be proposed.  In addition, basic research
projects must be included that relate to the clinical focus.  A SCOR
may also contain one or more core units that support the research
projects.

Length of SCOR Programs

Each NHLBI SCOR program is limited to 10 years of support.
Exceptions to this policy will be made only if a thorough evaluation
of needs and opportunities, conducted by a committee composed of
non-federal experts, determines that there are extraordinarily
important reasons to continue a specific SCOR program.

Under this policy, a given SCOR grant is awarded for a five-year
project period following an open competition.  Only one five-year
competing renewal is permitted, for a total of 10 years of support,
unless the SCOR program is recommended for extension.

The NHLBI comprehensive evaluation of the Pathobiology of Fibrotic
Lung Disease, Pathobiology of Lung Development, and Cellular and
Molecular Mechanisms of Asthma SCOR programs will be conducted during
the second project period according to the following timetable:

Program Announced                      FY 1994

Project Period (First Competition)     FY 1997 through FY 2001

Program Reannounced                    FY 2000

Project Period (Second Competition)    FY 2002 through FY 2006

Letter to SCOR Directors Regarding     FY 2003 (mid-way through year
02 of
 SCOR Evaluation Plans                  2nd project period)

SCOR Evaluation Meeting                FY 2004 (late in year 02 of
2nd project
                                        period)

Notification of SCOR Directors         FY 2004 (mid-way through year
03 of
 of NHLBI Decision                      2nd project period)

The NHLBI does not limit the number of SCOR applications in a given
SCOR program from one institution nor does it limit the number of
applications in the three SCOR programs described in this RFA from
one institution.  However, there must be a different SCOR principal
investigator for each application and each application must be
self-contained and independent of the other(s).  This does not
preclude cooperation planned or possible among participants of SCORs
after awards are made.  Scientific overlap among applications will
not be accepted.  If more than one application in a given program is
envisioned from an institution, the institution is encouraged to
discuss its plans with the NHLBI SCOR program administrator.

FUNDS AVAILABLE

Applicants may request up to $1,170,000 direct costs, not including
indirect costs for collaborating institutions, in the first year,
with a maximum increase of no more than four percent in each
additional year requested in the application.  Award of grants
pursuant to this RFA is contingent upon availability of funds for
this purpose.  It is estimated that a total of $28,000,000 will be
available for the first year of support for the three programs, and
it is anticipated that 14 awards will be made.

Equipment is included in the budget limitation.  However, requests
for expensive special equipment that cause an application to exceed
this limit may be permitted on a case-by-case basis following staff
consultation.  Such equipment requests require in-depth
justification.  Final decisions will depend on the nature of the
justification and the NHLBI's fiscal situation.

Consortium Arrangements

If a grant application includes research activities that involve
institutions other than the grantee institution, the program is
considered a consortium effort.  Such activities may be included in a
SCOR grant application, but it is imperative that a consortium
application be prepared so that the programmatic, fiscal, and
administrative considerations are explained fully.  The published
policy governing consortia is available in the business offices of
institutions that are eligible to receive Federal grants-in-aid.
Consult the latest published policy governing consortia before
developing the application.  If clarification of the policy is
needed, contact Mr. Ray Zimmerman, Grants Operations Branch, NHLBI,
301/594-7420.  Applicants of SCOR grants should exercise great
diligence in preserving the interactions of the participants and the
integration of the consortium project(s) with those of the parent
institution, because synergism and cohesiveness can be diminished
when projects are located outside the group at the parent
institution.  Indirect costs paid as part of a consortium agreement
are excluded from the limit on the amount of direct costs that can be
requested.

RESEARCH OBJECTIVES

Background

The SCOR program was initiated within the Division of Lung Diseases
in 1971 as a "Pulmonary SCOR."  Since then, several modifications and
changes in program direction have been made.  In the 1975 and 1980
competitions, the Division's SCOR program was announced in four
disease categories:  Chronic Airways Diseases, Fibrotic and
Immunologic Lung Diseases, Pediatrics, and Pulmonary Vascular
Diseases; in the 1985 competition the disease categories were:
Chronic Diseases of the Airways, Occupational and Immunologic Lung
Diseases, Respiratory Disorders of Neonates and Children, and
Pulmonary Vascular Diseases.  The SCOR program expanded in 1977 with
the solicitation for applications in Adult Respiratory Failure.  This
program was reannounced in 1982 and 1987, with the latter competition
resulting in four awards.  As a result of a Congressional mandate,
two new SCOR programs, Cardiopulmonary Disorders During Sleep and
Cystic Fibrosis, were announced in 1988, resulting in a total of five
awards.  Following an evaluation, a SCOR competition was announced in
1989 and the following awards were made in FY 1992:  three in Chronic
Diseases of the Lung and seven in Lung Biology and Disease in Infants
and Children.  In October 1992, a competition was announced in Acute
Lung Injury, Cardiopulmonary Disorders of Sleep, and Cystic Fibrosis.
In FY 1993, a total of six awards were made for centers in
Cardiopulmonary Disorders of Sleep and Cystic Fibrosis and six awards
were made in FY 1994 for centers in Acute Lung Injury.

In response to the new NHLBI policy that each SCOR program is limited
to 10 years of support, unless a programmatic evaluation indicates
that further support is warranted, the Division convened a committee,
composed of Pulmonary Diseases Advisory Committee members and ad hoc
consultants, to evaluate the SCOR programs in Occupational and
Immunologic Lung Diseases, Lung Biology and Disease in Infants and
Children, and Chronic Diseases of the Airways.  As a part of the
evaluation process, written and oral comments were received from the
current SCOR directors of these three programs.  As a result of this
evaluation, new SCOR programs were recommended in Pathobiology of
Fibrotic Lung Disease, Pathobiology of Lung Development, and Cellular
and Molecular Mechanisms of Asthma.

Proposed Research

Applications must be addressed to only one of the three disease
categories identified below to be acceptable for this competition.  A
SCOR grant is a five-year program, therefore, an applicant should
submit a five-year plan for all the projects.  If a project can be
completed in less than five years, it should not be included in the
application.

Examples of research topics of interest for each SCOR program under
competition are listed below.  These research topics are intended to
provide a perspective of the scope of research that would meet the
objectives of this program.  It is not required that all or any of
these topics be included; investigators are encouraged to consider
other topics that are relevant to the goals of these programs.

Pathobiology of Fibrotic Lung Disease

The SCOR program in Pathobiology of Fibrotic Lung Disease will focus
on cellular and molecular mechanisms involved in the transition from
the inflammatory events associated with early disease to the later
processes involving wound healing, repair, and fibrosis.  It will
offer the opportunity for in vitro, animal, and human studies on
diseases such as idiopathic pulmonary fibrosis, sarcoidosis, and
autoimmune-, occupational- and environmentally-induced lung disease.

Research aimed at identifying and characterizing prognostic factors
and molecular biomarkers of progression of disease is an important
aspect of this program.  Studies designed to obtain phenotypic
information that might be used to uncover the genetic basis of
susceptibility for developing pulmonary fibrosis would also
contribute significantly toward progress on understanding these
diseases.  Basic research on molecular/cell signalling, cell/cell
interactions such as those between epithelial cells and fibroblasts,
and the molecular basis for progression from the later stages of
inflammatory disease to fibrosis is a prime objective of this
program.

The most prominent manifestation of fibrotic pulmonary disease is the
abnormal accumulation of extracellular matrix components that results
in severe malfunctioning of the lungs.  The events that lead to an
exaggerated accumulation of these components in fibrotic lesions
involve a number of complex cellular and molecular processes, which
explains why the nature of both the inflammatory responses and the
triggering mechanism that induces the fibrotic response in the lung
remain poorly understood.  Cytokines and other factors are currently
recognized to play an important part in stimulating cells to
overproduce extracellular matrix components.  Following their initial
contact with the cell surface, these molecules are postulated to
activate intracellular signalling pathways, which in turn lead to
activation of a pleiotropic genetic program characteristic of the
fibrotic response.  This activation is thought to bring about changes
in the expression of specific genes that determine the phenotype of
cells involved in the healing of lung injury.  Research on specific
mechanisms that determine progression to aberrant healing of injury
and development of fibrotic lesions are an important area of interest
within this program.  Emphasis on molecular biologic and molecular
genetic technology is highly desirable to gain information on how the
transition from inflammation to normal healing and to fibrosis is
regulated in the lung.

During the past two decades, much information has been obtained at
the cellular and molecular level on the biology of connective tissue
formation and the pathophysiology of connective tissue diseases.  The
knowledge that pharmacologic interventions can be specifically
targeted at varying strategic points in the life cycle of
fibroproliferative processes has broadened considerably the realm of
therapeutic modalities that might be investigated to control these
processes.  Numerous approaches designed to control collagen
deposition remain untested in the lung.  Ways to overcome the
toxicity associated with collagen inhibitors through delivery methods
that exploit the unique aspects of the lung might be developed.
Experimentation that addresses collagen degradation, use of steroidal
and non-steroidal anti-inflammatory drugs, interferons and their
inducers, calcium and calmodulin antagonists, and cyclic nucleotides
also offers opportunities for continued development as ways to
control the accumulation of extracellular matrix in the lung.  The
SCOR program offers the opportunity for a multidisciplinary effort to
conduct in vitro studies, animal studies, and human studies aimed at
developing new ways to prevent and/or control fibrosis in the lung.

The SCOR program in the Pathobiology of Fibrotic Lung Disease also
offers the potential to compare and contrast mechanisms involved in
the fibroproliferative processes in diseases such as acute lung
injury and chronic obstructive lung disease with those of the chronic
interstitial lung diseases.

Pathobiology of Lung Development

The objective of this SCOR program is to expedite the acquisition and
application of new knowledge essential for improving clinical care of
infants and children with respiratory disorders.  The program will be
focused on delineating the sequence of events which occurs during
normal lung development and will include studies on the role of
genetic determinants as well as that of other factors that regulate
lung growth and repair.  An important goal of this program will be to
discern how the process of lung development is altered in several
important lung diseases of infants and children such as:
bronchopulmonary dysplasia (BPD), lung hypoplasia, persistent
pulmonary hypertension of the newborn, viral diseases in infancy and
early childhood and chronic bronchiolitis.

Although new clinical strategies, such as surfactant therapy, have
improved the outcome for infants born prematurely, the application of
the therapies has generated a hidden cost in the survival of lower
and lower birth weight infants. Along with the ability to keep low
birth weight infants alive, the incidence of chronic lung diseases in
infants, such as BPD, has increased dramatically by being able to
include that group.  The need to address the problems of this group
of infants presents a significant new challenge.

Because of the limitations in our knowledge, it is necessary to focus
upon an in-depth exploration of the pathobiology of early lung
development.  Currently available technologies of molecular
embryology should be utilized to ascertain the factors that control
growth and differentiation in the primitive lung bud and that
determine the repair options available to the developing lung in
models of lung injury.  Areas of specific research interest will
include:  lung molecular embryology; determinants of lung growth and
repair; genetic sequence of cell differentiation events; and the
etiology, prevention and management of clinical manifestations of
disordered lung growth.

Molecular embryology approaches may also be applied to the ontogeny
of the pulmonary vasculature and the etiology, prevention, and
management of clinical conditions such as persistent pulmonary
hypertension of the newborn.  Likewise, similar information on the
ontogeny of pulmonary defense mechanisms would be expected to
translate into the prevention and more effective management of
childhood pulmonary infections and bronchiolitis.

A systematic investigation of the molecular and cellular variables
defining the disordered growth observed in childhood lung disease
states, such as BPD, is required.  Of special interest will be the
identification of the complex of molecular variables involved in
normal lung development.  It is expected that a better understanding
of the process of lung development will lead to new interventions to
prevent arrested development of the lung via the translation of this
information into new clinical strategies.  Studies to elucidate the
relationship of early insults to lung development and subsequent lung
disease in childhood, adolescence and adulthood are encouraged.
Follow-up studies as well as the development of appropriate models of
injury or aberrant lung development are also encouraged.

Because the purpose of the program is to provide an opportunity for
the expeditious transmission of basic research results to the
bedside, the clinical problem should generate the research questions
within each SCOR program on Pathobiology of Lung Development.
Applicants will be encouraged to develop a comprehensive program of
well-integrated, mechanistic, basic research with high relevance to
the clinical focus of the SCOR grant.  For example, studies on the
efficacy and/or comparison of lung surfactant treatments in RDS will
not be considered responsive to this solicitation, whereas studies
concerned with the possible regulatory influence of the surfactant
proteins on early lung development could be considered responsive.

Cellular and Molecular Mechanisms of Asthma

The objective of this SCOR program is to better define the cellular
and molecular mechanisms underlying acute and chronic asthma through
multidisciplinary basic and clinical investigations.

Understanding the interaction and integration of various
inflammatory, immunologic, and neural processes and how they cause
the clinical syndrome of asthma is an important goal.  Cell
activation and cell-cell and cell-matrix interactions are poorly
understood in asthma, particularly as they relate to altered airway
function.  The role of specific inflammatory cells in the
pathogenesis of asthma requires further study.  The relationship
between influx of inflammatory cells and alterations in resident
airway cell function and tissue matrix is likely critical to this
process.  The influence of cytokines, adhesion molecules, and growth
factors also needs to be investigated.

Epidemiologic data strongly suggest that asthma results from the
combined effects of genetic and environmental factors, but the nature
of the gene or genes that contribute to this predisposition remains
to be established.  Molecular genetic studies of asthma require an
understanding of the complexity of phenotype and of the interactions
between genotype and the environment.  The availability of
longitudinal databases provides an essential component upon which to
base these types of studies.  Moreover, advances in molecular
genetics have produced useful systems that could be exploited to test
specific hypotheses that relate to asthma.  For example, transgenic
mice with specific alterations in protein expression may be useful to
determine the importance of individual factors (e.g., cytokines,
adhesion products, growth factors, membrane ion channels) in this
complex disorder.  While it is unlikely that any single genetic
manipulation would produce an animal with asthma-like disease, the
response of such model systems to airway inflammation might yield
important and specific information about normal host defenses and
pivotal regulatory molecules.  Use of these techniques provides the
possibility of determining how altered cell biology relates to airway
inflammation and asthma.

Mechanisms underlying the development and persistence of asthma, as
well as the processes resulting in the reemergence of active asthma
remain poorly understood.  Potential areas of investigation include
basic studies of the nature of the repair process in the airway wall
and of remodelling of the airway epithelium, connective tissue, and
airway smooth muscle; examination of potential sources of long-term
airway "memory", and development of in vivo systems demonstrating
persistent airway hyperresponsiveness.

Asthma changes with age yet little is known about the influence of
growth and development on lung physiology, immune function, and
features of bronchial hyperresponsiveness.  Investigations are needed
to better define the ontogeny of airway function (including airways
responsiveness), immune function, and inflammatory and neural control
mechanisms of potential relevance to asthma.

There is little doubt that inflammation is a component of asthma, but
the role of inflammation in the pathogenesis of the disease requires
further investigation.  The use of inhaled corticosteroids as
first-line treatment is likely to increase, and, although this
therapy has proven to be consistently efficacious, little is known
about the cellular and molecular mechanisms that contribute to the
clinical response.  This information is essential to the development
of therapeutic agents that possess the beneficial effects of inhaled
steroids without the undesirable side effects.  Another important
area of investigation is neural and immunologic mechanisms of
nocturnal asthma.  There is a need to better understand the circadian
aspects of physiology, bronchial reactivity, and inflammation.

Development and use of animal models, tissues, and cells derived from
the lung may be appropriate for certain studies, but, when feasible,
human lung materials should be employed.  In the case of studies with
non-human tissues or cells, the relationship of the proposed studies
to the improved understanding of human asthma and human airway
function relevant to asthma should be addressed.

SPECIAL REQUIREMENTS

Special features of SCOR grants are:

o  They provide opportunities for investigators with mutual or
complementary interests to engage in multidisciplinary research
focusing on a specific respiratory disorder.

o  Inherent in the SCOR program is a special interaction between the
SCOR director, the grantee institution and the Division of Lung
Diseases.  Funds are specifically allocated in a SCOR grant for
investigators from different SCORs to meet and discuss problems of
mutual interest and to participate in workshops addressing common
research areas.

o  The Division's overall SCOR program and each SCOR grant undergo
periodic evaluation.  The progress reports are prepared for the
information of the National Heart, Lung, and Blood Advisory Council,
the Division of Lung Diseases staff, and ad hoc members of SCOR
evaluation groups.

Requirements of SCOR grants:

o  Research conducted at the individual centers must include both
basic science and clinical research to ensure that advances in the
basic sciences are translated rapidly into clinical applications and
that clinical needs will provide a direction for the basic sciences.
Therefore, each SCOR grant application and award must include one or
more research projects involving human subjects/patients.  The basic
research projects should clearly relate to the disease focus and
contribute to elucidation of mechanisms underlying the disease, or to
improved diagnosis or management of the disease.

o  Each component project requires a well-described hypothesis,
preliminary data and a time-table for conducting the proposed
investigations.

o  If core facilities are included, the relationship of each
component project to each core should be described.

o  The principal investigator should be an established scientist with
the ability to ensure quality control and the experience to
administer effectively and integrate all components of the program.
A minimum time commitment of 25 percent is expected for this
individual.  The principal investigator must also be the project
leader of one of the component research projects.  If, through peer
review, this project is not recommended for further consideration,
the overall SCOR application will not be considered further.  If this
project is judged by peer review to be of low scientific merit, it
will markedly reduce the overall scientific merit ranking assigned to
the entire application by the review committee.

o  Project leaders must agree to commit at least 20 percent effort to
each project for which they are responsible.  Investigators with
minimal research experience, but promising credentials, may
participate; however, it is expected that most of the project
directors will be investigators with significant research experience.

o  Each SCOR must have a well-delineated organizational structure and
administrative mechanisms that foster interactions between
investigators, accelerate the pace of research, and ensure a
productive research effort.

o  If a project director transfers to another institution, support
for the project will normally not be continued as a consortium.

Because of the size and complexity of a SCOR, prospective applicants
are urged to consult with the staff of the Division of Lung Diseases
early in the preparation of the application (see INQUIRIES Section).
To provide opportunity for such interactions, the time frame for
implementation of this program includes an ample interval between the
release of this RFA, May 1994 and the receipt date for applications,
July 14, 1995.

STUDY POPULATIONS

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) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 9, 1994 (F 59 11146-11151), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 15, 1994, 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, it assists the
NHLBI staff to estimate the potential review workload and to avoid
conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 557
Bethesda, MD  20892

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research or may be obtained from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, MD 20892, telephone 301/435-0714 and from the NIH program
administrator named below.  Specific instructions for preparing a
SCOR application are available by contacting Director, Division of
Lung Diseases, as indicated under INQUIRIES.

The RFA label included in grant application form PHS 398 (rev. 9/91)
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 and number must be typed on
line 2a of the face page of the application form and the "YES" box
must be marked.

Send or deliver a signed, typewritten original of the application,
including the Checklist, and three signed photocopies, in one package
to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to Chief, Review Branch
at the address listed under LETTER OF INTENT.  It is important to
send these two copies at the same time as the original and three
copies are sent to the Division of Research Grants (DRG); otherwise,
the NHLBI cannot guarantee that the application will be reviewed in
competition for this RFA.

Applications must be received by July 14, 1995.  If an application is
received after that date, it will be returned to the applicant
without review.  The DRG 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 Division of Research Grants 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 application must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NHLBI staff.  Incomplete applications or
applications deemed not responsive to the RFA 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.  Applicants should submit the highest quality
applications possible to DRG as no site visits nor reverse site
visits are planned.  As part of the initial merit review, a process
(triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score, and
will also receive a second level of review by the National Heart,
Lung, and Blood Advisory Council.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
principal investigator and the official signing for the applicant
organization will be promptly notified.

Factors to be considered in the evaluation of each application will
be similar to those used in review of traditional research grant
applications and, in addition, will include overall proposed
interactions among basic and clinical research projects.  Major
factors to be considered in the evaluation of applications include:

o  Scientific merit of the proposed basic and clinical research
projects including significance, importance, and appropriateness of
the theme; innovation, originality, and feasibility of the approach;
and adequacy of the experimental design.

o  Leadership, scientific stature, and commitment of the program
director; competence of the investigators to accomplish the proposed
research goals and their time commitment to the program; and the
feasibility and strength of consortium arrangements.

o  Collaborative interaction among basic and clinical research
components, the balance between them, and plans for transfer of
potential findings from basic to clinical studies.

o  Adequacy of the environment for performance of the proposed
research including clinical populations and/or specimens; laboratory
facilities; proposed instrumentation; quality controls;
administrative structure; institutional commitment; and, when needed,
data management systems.

o  Appropriateness of the budget for the proposed program.

AWARD CRITERIA

The anticipated date of award is December 1, 1996.  Awards will be
made according to priority score, availability of funds, and
programmatic priorities.

INQUIRIES

Written and telephone inquiries concerning the RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.  Special supplemental instructions for the
preparation of grant applications for SCORs may be obtained by
contacting Director, Division of Lung Diseases, as indicated below.

Direct inquiries regarding programmatic issues to:

Suzanne Hurd, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A16
Bethesda, MD  20892
Telephone:  (301) 594-7430
FAX:  (301) 594-7408

Direct inquiries regarding fiscal matters to:

Raymond Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A17
Bethesda, MD  20892
Telephone:  (301) 594-7420
FAX:  (301) 594-7492

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, as
amended by Public Law 99-158, 42 USC 2241 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 Health Systems Agency
review.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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Research (OER)
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9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
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