Full Text HL-96-014
 
SCOR IN NEUROBIOLOGY OF SLEEP AND SLEEP APNEA, AIRWAY BIOLOGY AND
PATHOGENESIS OF CYSTIC FIBROSIS, AND ACUTE LUNG INJURY
 
NIH GUIDE, Volume 25, Number 23, July 12, 1996
 
RFA:  HL-96-014
 
P.T.  34

Keywords: 
  Pulmonary Diseases 
  Sleep Disorders 
  Injury 

 
National Heart, Lung, and Blood Institute
 
Letter of Intent Receipt Date:  December 13, 1996
Application Receipt Date:  July 22, 1997
 
PURPOSE
 
The primary objective of the Specialized Centers of Research (SCORs)
programs supported by the Division of Lung Diseases is to foster
multi disciplinary 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 sleep apnea, cystic fibrosis and acute
lung injury.
 
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 Neurobiology of Sleep and Sleep
Apnea, Airway Biology and Pathogenesis of Cystic Fibrosis, and Acute
Lung Injury, is related to the priority areas of diabetes and chronic
disabling diseases, unintentional injury, 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 nonprofit 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
to this announcement.  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 determined non-competitive, 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 Institutes of Health (NIH) specialized
centers (P50) mechanism to support this research program.  All
applications received in response to the Neurobiology of Sleep and
Sleep Apnea and Airway Biology and Pathogenesis of Cystic Fibrosis
programs will be considered as new applications.  Applications
submitted by current SCOR groups must be sufficiently changed to meet
the objectives of one of these programs.  Applications received in
response to the Acute Lung Injury program may be either new or
renewal applications.
 
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, which is defined as research conducted with
human patients/subjects or on material of human origin such as tissue
or other specimens for which an investigator directly interacts with
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 epidemiologic 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 Neurobiology of Sleep and
Sleep Apnea and Airway Biology and Pathogenesis of Cystic Fibrosis
SCOR programs will be conducted during the second project period
according to the following timetable:
 
Program Announced:                       FY 1996
 
Project Period (First Competition):      FY 1998 through FY 2003
 
Program Reannounced:                     FY 2001
 
Project Period (Second Competition):     FY 2003 through FY 2008
 
Letter to SCOR Directors Regarding
  SCOR Evaluation Plans:                 FY 2005 (mid-way through
year 02 of 2nd project period)
 
SCOR Evaluation Meeting:                 FY 2005 (late in year 02 of
2nd project period)
 
Notification of SCOR Directors of
  NHLBI Decision:                        FY 2006 (mid-way through
year 03 of 2nd project period)
 
This is the second competition for the Acute Lung Injury program 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 schedule:
 
Program Announced:                       FY 1991
 
Project Period (First Competition):      FY 1994 through FY 1998
 
Program Reannounced:                     FY 1996
 
Project Period (Second Competition):     FY 1999 through FY 2003
 
Letter to SCOR Directors Regarding
 SCOR Evaluation Plans:                  FY 2000 (mid-way through
year 02 of 2nd project period)
 
SCOR Evaluation Meeting:                 FY 2000 (late in year 02 of
2nd project period)
 
Notification of SCOR Directors of
  NHLBI Decision:                        FY 2001 (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
 
For new applications, the applicants may request up to $1,140,000
direct costs, not including indirect costs for collaborating
institutions, in the first year, and for renewal applications, the
applicants may request a 10 percent increase over the last year of
the preceding project period or a total of $1,140,000, whichever is
greater.  An increase of no more than four percent may be requested
in each additional year.  Award of grants pursuant to this RFA is
contingent upon availability of funds for this purpose.  It is
estimated that a total of $14,000,000 will be available for the first
year of support for the three programs and it is anticipated that 13
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 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.  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 DLD 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.
 
In 1989, the DLD announced a SCOR competition in Chronic Diseases of
the Airways, Occupational and Immunologic Lung Diseases, and Lung
Biology and Disease in Infants and Children, following an evaluation
of these programs.  The Division made a total of 14 awards in FY 1992
in these three SCOR categories.
 
An evaluation of the Pulmonary Vascular Diseases and Adult
Respiratory Failure SCOR programs resulted in the recommendation to
combine the two programs into a single new SCOR program in Acute Lung
Injury.  This new program was announced in 1991 along with renewal
programs in Cardiopulmonary Disorders of Sleep and Cystic Fibrosis.
In FY 1993, a total of seven 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 Institute 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.  The evaluation
resulted in new SCOR programs being announced in 1994 for
Pathobiology of Fibrotic Lung Disease, Pathobiology of Lung
Development, and Cellular and Molecular Mechanisms of Asthma.  Awards
will be made in FY 97 for these three programs.
 
An evaluation in 1995 by a group of consultants of the SCOR programs
in Cardiopulmonary Disorders of Sleep and Cystic Fibrosis resulted in
the recommendation that new SCOR programs be announced in
Neurobiology of Sleep and Sleep Apnea and in Airway Biology and
Pathogenesis of Cystic Fibrosis, two of the programs included in this
RFA.  The third program, Acute Lung Injury, is the renewal of a SCOR
program begun in FY 1994.
 
Justification for announcing a competition in the SCOR programs in
Neurobiology of Sleep and Sleep Apnea, Airway Biology and
Pathogenesis of Cystic Fibrosis, and Acute Lung Injury is based on
the recommendations from the SCOR evaluation, on past
accomplishments, which have been provided in reports from the
Division and the Institute, and on opportunities for new research
directions.  Funding for the Cardiopulmonary Disorders of Sleep and
Cystic Fibrosis centers expires on September 29, 1998 and for the
Acute Lung Injury centers on November 30, 1998.
 
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.
 
Neurobiology of Sleep and Sleep Apnea
 
The objective of this SCOR program is to integrate the molecular,
cellular and genetic approaches to sleep control with clinical
investigations on the etiology and pathogenesis of sleep disorders,
particularly sleep apnea.  The research topics identified below are
offered as examples that would be responsive to this announcement.
 
Recent advances in the cellular and molecular neurobiology of sleep
offer new opportunities to study the basic mechanisms of sleep and
the consequences of disturbed sleep (e.g., sleepiness, hypoxia, and
cardiovascular disease).  Studies directed at understanding the
fundamental neurophysiologic/pharmacologic, neuroanatomic, cellular
and molecular nature of sleep regulation and homeostasis; interaction
of CNS mechanisms involved in the regulation of sleep/wake states;
and the relationship between putative sleep modulators and the
pathogenesis of cardiopulmonary disturbances during sleep are areas
that need further study.
 
Genetic expression of neuromodulators and mediators during normal
sleep and in sleep apnea is another area that requires more
attention.  For example, molecular approaches should be applied to
determine what neurons express sleep promoting genes, whether sleep
apnea causes changes in gene transcription, and to elucidate the
regulatory signals involved in these genetic events.  It is also
important to determine how levels of sleep promoting compounds are
genetically controlled in the sleep/wake cycle, and whether
experimental alterations of specific genes alter sleep behavior.  It
is now known that homeostatic and circadian factors contribute to
regulation of sleep and wakefulness.  It is important to understand
the interaction between biological clocks, chronobiology and
sleep/wake behaviors at the cellular and molecular level, as well as
determine how the neural circuits in the brain respond to input from
the circadian pacemaker.  Studies are also needed to investigate
whether apoptosis and other neurodegenerative processes in
sleep-related brain regions contribute to the respiratory
disturbances.  Pharmacologic agents, implants of
genetically-engineered cells and gene transfer technologies need to
be considered.
 
Sleep disordered breathing and snoring have been implicated as risk
factors for the development of  hypertension, ischemic heart disease
and cerebral infarction.  It is important to examine the
pathophysiology of sleep apnea in relation to cardiovascular
diseases.  There is also a need for more vigorous basic research
directed towards understanding the autonomic nervous system, central
cardiovascular control, and the neurophysiologic and
neuropharmacologic mechanisms that regulate cardiovascular and
circulatory adjustments during sleep.
 
Epidemiologic studies have provided new insights into the prevalence
of sleep apnea.  Studies are needed to better define sleep apnea,
identify possible sleep phenotypes and determine its predictors and
antecedents, particularly in its early phases.  One important
question is what is the effect of sleep apnea in childhood on
development of sleep disorders in later life?  Evidence now suggests
that the nature of sleep disturbances due to sleep apnea in children
may be different than in adults.  Attention should be given to the
relationship between pathologic and physiologic abnormalities, gender
specific factors and the impact of sleep apnea in children and the
family.  Better objective measures and standardized criteria for
sleep apnea, including the associated morbidity and mortality should
be investigated.
 
Since excessive daytime sleepiness is a major clinical consequence of
sleep apnea, it is important to focus on the basic neural mechanisms
that produce sleepiness and design new approaches to evaluate daytime
performance/alertness and sleepiness.  Critical assessment of
therapeutic approaches and development of new therapeutic strategies
for sleep disorders, particularly pharmacologic approaches remain
important goals of this SCOR program.
 
Airway Biology and Pathogenesis of Cystic Fibrosis
 
Despite dramatic advances in our understanding of the molecular and
cellular basis of CF, our knowledge of the biology, structure and
function of CFTR remains superficial.  There is a critical need to
begin to translate our current knowledge of CFTR into the broader
aspects of airway biology, the pathogenesis of CF, and the
development of new pharmacologic or gene therapies.  The objective of
the SCOR program is to utilize our current knowledge of CFTR as a
focus of information, to promote advances in research on the
pathogenesis of CF, the role of CFTR in airway biology, and the
development of new treatment strategies. CF lung disease is
characterized by chronic bacterial infections and inflammation that
progressively destroy the lung.  Yet it is not understood how a
defect in CFTR leads to this bacterial colonization and inflammation.
Information on how CF begins and progresses in the airway with
respect to inflammation and/or infection is particularly important.
Also critical is an understanding of the role of host defense
mechanisms and inflammatory mediators in preventing or contributing
to pathogenesis.  How the loss of CFTR alters airway function is
poorly understood.  The airway surface fluid (ASF), believed to play
a role both in fetal lung development and in adult pulmonary
homeostasis and defense, may be critical in influencing lung
function.  Yet, our overall understanding of the mechanisms which
generate and control ASF, and how CFTR affects it, is still lacking.
ASF includes contributions from the submucosal glands; serous gland
cells within the submucosal glands have been shown to contain large
quantities of CFTR.  Thus, an evaluation of the contribution of the
submucosal glands versus the surface epithelium in normal fluid and
electrolyte balance and in the pathogenesis of CF is needed.
Developmental issues regarding fluid and electrolyte balance and
information on stem or progenitor cells are also critical to our
understanding of basic aspects of lung biology and would be helpful
for therapeutic approaches.
 
The role of CFTR plays in human airway epithelial function needs to
be better defined.  Critical to our understanding of how mutations in
CFTR cause disease are structural biology studies both on mutant and
wild-type CFTR.  CFTR is known to function as a chloride channel and
as a regulator of both sodium and chloride channels.  Yet issues
remain unresolved regarding the intramolecular and intermolecular
interactions of different domains of CFTR, functional control of
airway processes including ion transport, infection and inflammation,
and consequences of mutations to the function of CFTR and the
pathogenesis of CF.  As potential sites of therapeutic targets
designed to provide alternate pathways for fluid production in CF
airways, it would be important to study alternate ion channels,
uncover new receptors which control lung function and develop methods
of overcoming aberrant processing of mutant CFTR.
 
Despite the new information on the primary defect in CF, there are
still no new therapies which correct the primary defect or activate
alternative pathways to prevent airway disease.  Thus, there is a
critical need to translate the new knowledge regarding the
pathogenesis of CF and the function of CFTR into new treatment
strategies.  Thus, the development of novel pharmacologic and gene
therapies focusing on the primary consequences of CF (i.e., defective
CFTR) would be important, such as the development of agents which
correct defective CFTR or which interfere with bacterial
colonization.  Several barriers to persistent correction of defective
CFTR function such as vector-induced inflammation and low efficiency
of airway cell transduction, have been identified. Thus, new
strategies to overcome these barriers and to prevent inflammation are
needed.  Identification of appropriate lung cell targets for gene
transfer such as progenitor, surface and submucosal gland cells is
needed.
 
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. When warranted, research
involving human patients/subjects is preferable.
 
Acute Lung Injury
 
The pathogenesis of acute lung injury/acute respiratory distress
syndrome (ALI/ARDS) is thought to be related to an over-reaction of
the inflammatory/immune system.  In sepsis, a frequent predecessor to
ARDS, a sequence of mediator responses has been clearly documented,
and agents have been created that block the activity of the
mediators.  Although these agents are  protective in animal models,
clinically useful and specific therapies have not been found.  This
is in part because the inflammatory response has turned out to be
much more complex than originally thought. Particularly important,
now that many mediator systems have been identified, is to determine
the interactions between the various systems.
 
Promising areas for new insights may be found from studies of the
relationship between inflammatory cell activation, surface adhesion
molecules, and signal transduction; the interaction of oxidants with
nuclear transcription factors; the mechanisms by which endotoxin
increase intracellular oxidants; and the molecular mechanisms through
which surfactant proteins modify nitrosation reactions remain to be
characterized.  The barrier and metabolic functions of the
endothelium are disturbed during ALI and the molecular determinants
of these processes need to be delineated.  Similarly, progress has
been made in the description of ion channels in the alveolar
epithelium; however, the exact structure and function are unknown.
The determinants of cell death and recovery need to be examined as do
the factors that promote fibrosis as opposed to healing after tissue
injury.
 
Studies with knockout animals have shown that absence of adhesion
molecules from birth does not alter the inflammatory response.
However, the inflammatory system is redundant and these experiments
do not prove that alterations in adhesion molecules are not important
in human disease.  ALI/ARDS is an acute and acquired disease.  Models
using inducible promoters would allow for manipulation of mediator
levels throughout the course of the disease.
 
Animal models are needed that accurately reflect human disease. In
this regard, multidisciplinary studies that are directed towards
understanding the integrated response of the entire organism to lung
tissue injury may be particularly useful.  Multiple Organ Dysfunction
Syndrome (MODS), a frequent cause of death during ARDS, is
particularly suited to whole animal studies where the integrated
response of the whole organism can be studied.  For example, the lung
is known to produce large amounts of glutamine, an important gut
nutrient.  In sepsis, release of glutamine from the lung increases,
but as ARDS develops, the release of glutamine from the lung drops
precipitously, possibly affecting intestinal metabolism and
viability, and furthering progression of MODS. Other interactions
between the lung and other organs and their contribution to ARDS
pathogenesis need to be elucidated in both animals and humans.
 
Many questions remains about the progression and natural history of
ALI/ARDS.  There is a need to evaluate the role of inflammatory
mediators in humans while controlling for confounding variables such
as comorbidities, duration of disease, and physiologic variables.
Other aspects of pathophysiology, including tissue oxygenation and
metabolism, need to be investigated in patients as well as in the
laboratory.  Recently, two gene products of tumor necrosis factor
(TNF) have been identified in humans, and the presence of homozygous
TNFB2 gene as opposed to TNFB1 predicted the outcome of patients with
sepsis.  More needs to be done to evaluate possible genetic control
of the response to tissue injury in humans.
 
A clinical core is required to provide the following functions:
enroll and characterize all ALI/ARDS patients; provide access to
patients and patient samples for the research projects; and
facilitate coordination within a SCOR center and among the ALI SCOR
centers.
 
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 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 research.
Therefore, each SCOR grant application and award must include one or
more research projects involving human patients/subjects. 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 RFA, June 1996 and the receipt date for applications,
July  22, 1997.
 
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 (F59 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 13, 1996, 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
Two Rockledge Centre, Suite 7093
6701 Rockledge Drive, MSC 7924
Bethesda, MD  20892-7924
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) 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,  Office of Extramural Outreach and
Information Resources, National Institutes of Health,  6701 Rockledge
Drive, MSC 7910 Bethesda, MD  20892-7910 Telephone:  (301) 435-0714
Email asknih@odrockm1.od.nih.gov. and from the NIH program
administrator listed under INQUIRIES.  Specific instructions for
preparing a SCOR application are also available from the program
contact listed under INQUIRIES.
 
The RFA label included in grant application form PHS 398 (rev. 5/95)
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.
 
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
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
 
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 22, 1997.  If an application is
received after that date, it will be returned to the applicant
without
review.  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 applications 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 will be held.  As part of the initial merit review, a
streamlined process 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 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 September 30, 1998 (FY 1998) for the
Neurobiology of Sleep and Sleep Apnea and Airway Biology and
Pathogenesis of Cystic Fibrosis programs and December 1, 1998 (FY
1999) for the Acute Lung Injury program.  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.
 
Direct inquiries regarding programmatic issues and requests for
supplemental instructions to:
 
Suzanne Hurd, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0233
FAX:  (301) 480-3547
Email:  hurds@gwgate.nhlbi.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Raymond Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  zimmermr@gwgate.nhlbi.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.838.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 U.S.C. 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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