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

Release Date:  September 27, 1999

RFA: HL-00-001

National Heart, Lung, and Blood Institute

Letter of  Intent Receipt Date:    January 7, 2000 
Application Receipt Date:          August 30, 2000 

PURPOSE

The primary objective of the Specialized Center of Research (SCOR) 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 Request for Applications (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 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)
or at http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit or nonprofit domestic
institutions, public or private, such as universities, colleges, hospitals,
and laboratories.  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.  Racial/ethnic minority
individuals, women and persons with disabilities are encouraged to apply as
Principal Investigators and as project leaders.  This RFA is intended to
support SCOR grants for basic and clinical investigations.  Therefore,
applications that include only basic or only clinical research will not be
responsive to this RFA.  In addition, clinical research projects
focused on large epidemiologic studies or large clinical trials will be
considered unresponsive to this RFA.

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.  New and renewal applications
will be responsive to this RFA.  

Responsibility for the planning, direction, and execution of the proposed
research 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 5 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 5-year project period
following an open competition.  Only one 5-year competing renewal is
permitted, for a total of 10 years of support, unless the SCOR program is
recommended for extension.

This is the second competition for these three SCOR programs and, therefore,
will undergo a comprehensive evaluation during the second year of the upcoming
project period.  The evaluation will be conducted 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           
  SCOR Evaluation Plans:                          FY 2003 (mid-way through
year 02 of
                                                       2nd project period)

SCOR Evaluation Meeting:                     FY 2003 (late in year 02 of 2nd   

                                                       project period)

Notification of SCOR Directors 
  of NHLBI Decision:                         FY 2004 (mid-way through year 03
of
                                                       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 announcement 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 $1,350,000 direct costs, not including facilities
and administrative costs (F&A) for collaborating institutions, in the first
year with a maximum increase of no more than 3 percent in each additional year
requested in the application.  Award of grants pursuant to this RFA is
contingent upon receipt of funds for this purpose.  It is estimated that a
total of $26,000,000 will be available for the first year of support for the 3
programs and it is anticipated that up to 15 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 requires in-depth justification.  Final decisions will depend on the
nature of the justification and the Institute'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, 301 435-0171.  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.  F&A
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

These SCOR programs focus on three disease areas: fibrosis associated with
chronic interstitial lung disease; diseases in the newborn related to abnormal
lung development and premature birth; and asthma.  All of these diseases
remain major public health problems with associated high morbidity and
mortality.  Emphasis will be placed on understanding these disease processes
at the cellular and molecular levels taking advantage of such state of the art
approaches as genomic technologies and informatics that are now available.  In
addition, these SCORs  will enable investigators to readily translate their
basic research findings to clinical application in well characterized patient
populations.  

The first SCOR program initiated within the Division of Lung Diseases was in
1971 and was entitled  Pulmonary SCOR. Since then, several modifications and
changes in program direction and focus have been made.  In the 1975 and 1980
competitions, SCOR programs were announced in four disease categories: 
Chronic Airways Diseases, Fibrotic and Immunologic Interstitial Lung Diseases,
Pediatric Pulmonary Diseases, 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, resulting in five and four
awards, respectively.  In response to a congressional mandate, two new SCOR
programs, Cardiopulmonary Disorders of Sleep and Cystic Fibrosis, were
announced in 1988, resulting in three awards in each program. 

Following an evaluation, a SCOR competition was announced in 1989 in three
programs: Chronic Diseases of the Airways, Occupational and Immunologic Lung
Diseases, and Lung Biology and Disease in Infants and Children, with three,
four and seven awards being made, respectively.  Upon the recommendation of an
ad hoc advisory group, the Adult Respiratory Failure and Pulmonary Vascular
Diseases programs were combined and a new program in Acute Lung Injury was
announced in 1991, with six awards being made.  Also in 1991, Cardiopulmonary
Disorders of Sleep and Cystic Fibrosis were reannounced, resulting in three
awards in Cardiopulmonary Disorders of Sleep and four awards in Cystic
Fibrosis.  Following a SCOR evaluation, new SCOR programs were announced in
1996 in Neurobiology of Sleep and Sleep Apnea and in Airway Biology and
Pathogenesis of Cystic Fibrosis, with four awards being made in each program. 
The Acute Lung Injury program was also reannounced in 1996, resulting in seven
awards.  

The National Heart, Lung, and Blood Institute implemented a new policy in 1992
that a SCOR program can be supported for a maximum of 10 years, unless the
outcome of a programmatic evaluation indicates that further support is
warranted.  To address this policy, 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 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.  It is the reannouncement of
these three programs for the second 5-years of funding that is the subject of
this RFA.

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 5
year program, therefore, an applicant should submit a 5 year plan for all the
projects.  If a project can be completed in less than 5 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 

Pulmonary fibrosis is a disease of unknown etiology and has a devastating
course.  Initiating events are unknown and patients are diagnosed at a stage
where little can be done to reduce the morbidity they suffer or prevent their
death due to the disease.  For example, the mortality from idiopathic
pulmonary fibrosis is approximately 50 percent within 5 years of diagnosis. 
Investigations of this disease are still at a very early and basic stage.  The
goal of this SCOR program is to increase our knowledge of the disease through
laboratory and clinical investigations, with a focus on identifying initiating
events, early clinical symptoms, underlying pathogenic mechanisms, and
interventions which can slow or reverse the progressive replacement of normal
lung tissue with fibrotic tissue.  Since fibrosis can appear in a number of
chronic interstitial diseases, this program offers 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.

Although the underlying pathogenic mechanisms involved in disease development
and progression have benefitted from considerable attention, additional work
is required in order to understand the events involved.  Pulmonary fibrosis is
characterized by replacement of normal lung architecture by fibrotic tissue. 
The events that lead to an exaggerated accumulation of fibroblasts, collagen,
and extracellular matrix involve a number of complex cellular and molecular
processes.  The nature of both the inflammatory responses and the triggering
mechanism that induce the fibrotic response in the lung remain poorly
understood.  More information is needed about how the normal regulation of
fibroblast proliferation and activation and collagen synthesis has been
subverted.  Metalloproteinases are involved in altering connective tissue
matrix and remodeling. Their role in pulmonary fibrosis pathogenesis needs to
be further defined.  A role for apoptosis and the Fas-Fas ligand pathway in
fibrosis also deserve additional investigation.  How fibroblasts act as
"sentinel" cells and initiators of events leading to fibrosis, and the
existence and participation of fibroblasts with unique phenotypes in fibrotic
lesions are also areas of interest.  The potential role for an autoimmune
response and infectious agents in the etiology of pulmonary fibrosis and other
interstitial lung diseases are also areas that are relevant to this program.

Prime objectives of this program include: further exploration of molecular and
cellular interactions between immune and inflammatory responses, fibroblasts,
macrophages, and lymphocytes, growth factors, and intracellular signaling
pathways in pulmonary fibrosis.  Cytokines and other molecular factors act on
cells via specific receptors and result in the expression of new genes and
gene products that contribute to a fibrotic response.  Investigation of the
nature of such cell-surface receptors, subsequent intracellular signaling,
regulation of gene expression at the translation and transcription level, and
identification of transcription factors are areas that are relevant to this
SCOR program.  Investigation of changes in the expression of specific genes
that result in aberrant healing of injury and development of fibrotic lesions
are important areas of interest within this program.  Identification of
biomarkers in blood or bronchoalveolar lavage fluid that would assist in an
earlier diagnosis and disease status or progression would be very useful. 
Although there are animal models that are used in fibrosis research, many
suffer from "contamination" with characteristics more similar to acute lung
injury.  Fibrosis research would benefit from the availability of an animal
model of pulmonary fibrosis that more closely resembles the human disease.

Steroids have been used as the standard treatment of pulmonary fibrosis.  They
are inadequate by many parameters - they do little to affect the disease
course and have very serious adverse side-effects that can add to the
morbidity caused by the disease.  Pilot clinical studies to identify and
test new interventions are an important part of this SCOR program.  The
ability to specifically target strategic points in the fibrotic process
suggests that new interventions may be successful by interfering with
fibroproliferation and collagen deposition.  The wide range of other
compounds that may be beneficial therapeutically include: suramin, relaxin,
prostaglandin-E2, leukotriene antagonists and inhibitors of leukotriene
synthesis, captopril and other angiotensin converting enzyme inhibitors, and
angiotensin II receptor antagonists. The SCOR program, through the clinical
component, provides the opportunity to conduct pilot trials.

This SCOR program also provides an opportunity to conduct small scale pilot
population-based studies.  Pilot studies to determine how to systematically
collect, in a standardized way, such information as medical and family history
for use in identifying risk factors, the earliest events in the disease
course, or the cause(s) of the disease would make a significant contribution
to understanding the disease.  Similarly, coordinated standardized collection
of biological specimens (e.g., blood, bronchoalveolar lavage fluid and cells,
biopsy tissue and slides) in association with clinical data could be a
valuable resource for testing hypotheses.  Although systematic large-scale
investigations of the role for environmental exposures, infectious agents,
or genetic susceptibility contributions to the disease are beyond the scope of
this SCOR program, pilot studies could provide a basis for larger scale
case-control studies of the etiology of pulmonary fibrosis, similar to the
NHLBI-supported study in sarcoidosis (ACCESS).  Pilot studies could also
provide the basis for future studies of the possible interaction of
environmental and genetic factors and the natural history of pulmonary
fibrosis.

Pathobiology of Lung Development

Bronchopulmonary dysplasia (BPD) is a disease of disordered lung growth
characterized by abnormal size and shape of alveoli. The increased incidence
of this chronic lung disease, which has accompanied the increased survival of
very low birth weight infants and which develops over time ex utero, has
identified it as a developmental disease.  Likewise, persistent pulmonary
hypertension of the newborn (PPHN) represents a failure to achieve the
maturational transition in vascular resistance, while lung hypoplasia is a
manifestation of arrested lung growth.  The mechanisms underlying the
development of these diseases are complex but, now, technologically
approachable.  The objective of this SCOR program continues to be the
acquisition and application of new knowledge essential for improving clinical
care of infants and children with developmental respiratory disorders.  An
important goal of this program will be to discern how the process of lung
development is altered in lung diseases of infants and children such as BPD,
PPHN, lung hypoplasia and chronic bronchiolitis.

In recent years, molecular tools have been developed which permit lung
biologists and research neonatologists to re-visit the embryology of the lung
in molecular terms.  We should now be able to delineate the sequence of events
that occurs during normal development of the lung organ system so that an
instance of pathologic lung development may be identified as a consequence of
an altered determinant that results in a specific negative event or cascade of
negative events.  Therefore, characterization of abnormal lung development is
dependent upon the profile of the normal lung, its vasculature, and its immune
system.  Identification of genetic determinants of structure and of growth
factors and tissue cytokines which are involved in regulating growth and
structural/functional differentiation of the lung would be an important part
of the profile. Other pharmacologic agents which could augment structure,
stimulate lung growth or enhance function might be identified or developed on
the basis of this information.

Delay of maturation of both cellular and local mucosal immune function can
initiate inflammatory processes in the course of lung development which, in
turn, negatively impact on the process of lung development.  Studies concerned
with the effect of pre- and post-natal infection and reactive inflammation on
the subsequent course of lung development and during the fragile stages of
lung maturation in infancy and early childhood would provide information
concerning the development of immunity in the lung as a factor in both
immediate lung development and long-term lung function.  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 chronic bronchiolitis.  

The mechanisms involved in the systematic orchestration of the formation of
new vessels in the developing embryo, followed by cessation of further
vascular proliferation, represent an important area of overlap between organ
development (vasculogenesis) and the repair of injured tissue (angiogenesis). 
Control of vascularization is a cross-cutting area of science with
implications for organ development, tissue repair and disease processes.  The
fundamental relationship between angiogenic/angiostatic modulation in the
developing vasculature and in organ development should be examined in the
lung.  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 PPHN. 

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 relevant models
of aberrant lung development are also encouraged.  Rational therapeutic
intervention should be explored, if possible, in situations where some aspect
of abnormal growth and differentiation can be identified as a significant
feature of the clinical disease.  The development of profiles and screens for
reliable prognostic assessment of disease is also encouraged.

Cellular and Molecular Mechanisms of Asthma
 
Asthma is a chronic, often life-long disease with increasing prevalence,
morbidity and mortality.  The complexities of human asthma are only now
becoming fully appreciated.  The focus of this SCOR reannounncement continues
to be the delineation of the cellular and molecular mechanisms underlying
acute and chronic asthma through multidisciplinary basic and clinical
investigations.
 
Inflammation, hyperresponsiveness, and airflow obstruction are the hallmarks
of asthma and thought to result from multiple, independent, or interacting
pathways involving genetic, environmental and inflammatory phenomena.  The
molecular mechanisms leading to asthma heterogeneity require investigation as
well as the parameters that differentiate atopic patients with and without
asthma.  Elucidating the cellular and molecular mechanisms leading to and
relationship between chronic inflammation, airway remodeling and repair,
airways hyperresponsiveness, persistence of asthma, and the fixed and
reversible airway obstruction associated with asthma, are important goals of
this program.  Of specific interest are studies on the potential sources of
long-term airway "memory" cells; events regulating the function of
recruited and resident airway cells;  the role of cytokines, adhesion
molecules, growth factors and proteases in mediating the physiologic or
anatomic changes seen in chronically inflamed airways; cell-cell and cell
matrix interactions; the role of innate immunity in the
initiation/perpetuation of airway inflammation;  mechanisms leading to mucous
cell and goblet cell hyperplasia and mucus hypersecretion;  how all of the
these changes influence the natural history of asthma; and how they can be
therapeutically arrested or prevented.  Identification of biomarkers of
inflammation that reflect disease activity are needed to help monitor the
progression of asthma and the effectiveness of therapy.  If the aberrant
cellular activities leading to asthma are due to dysfunction of cell receptor
signaling mechanisms, it will be important to establish the cellular,
molecular, and  physiologic basis of receptor/signal transduction dysfunction
in asthma. 

Maternal, fetal, immune, infectious and other factors involved in the onset
and development of asthma early in life and its persistence or reemergence in
later life are incompletely understood.  Childhood infections have been
postulated to play a role, either causative or protective, in the development
of childhood asthma.  It is important to establish how some respiratory
pathogens contribute to development and exacerbation of, or the protection
from childhood asthma, including the effects of the timing, duration, and
frequency of exposure to infections, their interaction with allergens,
influence on the immune system, and the potential impact of early treatment
with antibiotics on the development of the disease and its sequelae. 

Progress is being made in establishing the chromosomal location for some of
the asthma associated genes.  However, identification of asthma associated 
gene(s), either contributing to predisposition to asthma, the development and
regulation of airway inflammation and remodeling, modifying the course of the
disease, or patient's response to therapy remains to be established.  The
availability of existing longitudinal and clinical databases provides an
essential component to base studies of gene-gene and gene-environment
interactions.  Molecular genetic techniques and high throughput gene
expression technologies with sophisticated informatics need to be brought into
asthma research to help advance the goal of identifying asthma associated
genes, reasons for their altered expression, and the nature and function of
the proteins for which they code. 

Studies in human subjects and with human materials, especially children and
young adults, are strongly encouraged.  Large epidemiologic studies or
clinical studies requiring longer than 5 years will not be supported under
this announcement.  Appropriately designed in vitro and in vivo studies with
animal models are encouraged, but must be relevant to asthma and suitable for
addressing the mechanistic information sought in this solicitation.  Use of
state of the art genomic technologies and informatics is especially encouraged
where appropriate, to accelerate research on asthma pathogenesis and
treatment. 

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 assure 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 mechanism 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 announcement
and the receipt date for applications.  All applications must be prepared
according to the Special Instructions that are available from the Director,
Division of Lung Diseases (see INQUIRIES Section).

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 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
"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, available on the web at:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS

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

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 7, 2000, 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:

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

APPLICATION PROCEDURES

The research grant application form PHS 398, rev. (4/98), is to be used in
applying for these grants.  These forms are available at most institutional
offices of sponsored research or may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, Maryland  20892-7910, telephone
(301) 435-0714, E-mail: GrantsInfo@nih.gov.  Special 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. 4/98) 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 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. 

Send or deliver 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
Two Rockledge Centre
6701 Rockledge Drive, Room 1040
Bethesda, Maryland  20892
Bethesda, Maryland  20817 (for express/courier service)

Send two additional copies of the application to C. James Schreirer, Ph.D. 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
Center for Scientific Review (CSR); otherwise, the NHLBI cannot guarantee that
the application will be reviewed in competition for this RFA.

Applications must be received by August 30, 2000.  If an application is
received after that date, it will be returned to the applicant without review. 
CSR will not accept any application in response to this RFA that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The CSR will not accept any
application that is essentially the same as one already reviewed.  This does
not preclude the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by 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 CSR as no site visits or 
reverse site visits will be held. As part of the initial merit review, a 
streamlined process may be used by the initial review group in which the scientific
merit of applications relative to other applications received in response to
the RFA will be determined.  Applications judged to be of high scientific merit 
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 of low scientific merit will be withdrawn from 
further consideration and the principal investigator and the official signing for
the applicant organization will be 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, 2001.  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.  Anyone submitting a grant application must
follow the special supplemental instructions for preparing an application.

Direct inquiries regarding programmatic issues to:

Suzanne Hurd, Ph.D.
Director, Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10018, MSC 7952
Bethesda, Maryland  20892
Telephone:  301 435-0233
FAX:  301 480-3547
E-mail: Hurds@nih.gov

Direct inquiries regarding fiscal matters to:

Raymond Zimmerman
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154, MSC 7926
Bethesda, Maryland  20892-7926
Telephone:  301 435-0171
FAX:  301 480-3310
E-mail: ZimmermR@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.838.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, 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 PHS strongly encourages all grant and contract 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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