GENOMIC APPLICATIONS FOR HEART, LUNG, AND BLOOD RESEARCH

Release Date:  July, 29, 1999

RFA:  HL-99-024

National Heart, Lung, and Blood Institute

Public Briefing Date:  November 19, 1999
Letter of Intent Receipt Date:  January 10, 2000
Application Receipt Date:  March 14, 2000

PURPOSE

The intent of this Request for Applications (RFA) is to establish Programs for
Genomic Applications (PGAs) for Heart, Lung, and Blood Research.  The goal of
the PGAs is to link, on a genomic scale, the resources and tools of the Human
Genome Project (HGP) to major biological processes and systems involved in
cardiovascular, pulmonary, hematologic, and sleep function and dysfunction.

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, Genomic Applications for
Heart, Lung, and Blood Research, is related to one or more of the priority
areas.  Potential applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of
the Federal government.  Foreign institutions are ineligible from receiving
awards under this solicitation.  However, under exceptional circumstances, a
foreign component critical to a PGA may be included as a part of that program. 
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

The National Institutes of Health (NIH) grants policy statement will apply to
grants awarded under this RFA.

Multiple applications may be submitted from a single institution; however, the
Principal Investigator, focus, theme, and technology must differ between the
applications.  In the event that more than one application at a single
Institution is funded, the NHLBI will work with those sites to reduce or
eliminate redundancy of work, and structure the most cost effective program.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) administrative and funding
mechanism of support.  Under the cooperative agreement, the NIH assists,
supports, and/or stimulates, and is substantially involved with recipients in
conducting a study by facilitating performance of the effort in a "partner"
role.  Details of the responsibilities, relationships, and governance of a
study funded under a cooperative agreement are discussed later in this
document under the section entitled SPECIAL REQUIREMENTS.

The total project period for an application submitted in response to this RFA
may not exceed four years.  A one-time competitive renewal, for the existing
awardees, may be awarded for an additional four years, for a maximum of eight
years of support.  This RFA is a one-time solicitation.  The anticipated award
date is September 30, 2000.

FUNDS AVAILABLE

The NHLBI intends to commit up to approximately $35,000,000 in FY 2000 to fund
up to 10 new PGAs in response to this RFA.  An applicant may request a project
period of up to 4 years and a budget for total costs (direct costs plus
facilities and administrative (F&A) costs) of up to $3,500,000 per year,
including F&A costs on consortium arrangements.  Because the nature and scope
of the research proposed may vary, it is anticipated that the size of each
award will also vary.  Although the financial plans of the NHLBI are to
provide support for this program, awards pursuant to this RFA are contingent
upon the availability of funds and the receipt of a sufficient number of
applications of outstanding scientific and technical merit.  At the end of the
first project period, if funds are available, applications for renewal will be
accepted for up to an additional four years of support.  Designated funding
levels are subject to change at any time prior to final award, due to
unforeseen budgetary, administrative, or scientific developments.

RESEARCH OBJECTIVES

Background

The Human Genome Project (HGP) has produced vast amounts of data,
technologies, and resources at a rate far exceeding the capacity of individual
investigators to use them.  The essential next step in this genomic era is to
couple these data, technologies, and resources with the biology and
pathophysiology that define heart, lung, blood, and sleep health and disease,
ranging from epidemiology and prevention to cellular and molecular studies.

Heart, lung, and blood diseases are extremely complex human conditions that,
until recently, have been viewed from the perspective of only one or a few
genes operating at a time.  With the progress of the HGP we will soon be able
to examine all 50,000 -100,000 human genes and attempt to relate them to
research questions relevant to heart, lung, and blood disorders.  The
development of a program to functionally characterize and categorize genomic
data and identify those subsets of genes and gene products that are of
particular relevance to heart, lung, and blood disorders, will facilitate and
accelerate development of new therapeutic, preventive, and diagnostic
strategies by enabling individual investigators to access more defined and
manageable data sets.

The NHLBI proposes to initiate the Programs for Genomic Applications (PGAs) to
begin to assign function to the genome for heart, lung, and blood diseases and
sleep disorders.  The principal goal of the NHLBI PGAs will be to link genes
to function on a genomic scale in order to facilitate investigations in
physiological and pathophysiological mechanisms underlying heart, lung, blood,
and sleep function and disease.  The analysis of genome variation linked to
disease, genome-wide mutagenesis and phenotypic screens, and variable
expression studies using array technologies are a few of the approaches that
can be used to identify subsets of genes relevant to heart, lung, blood, and
sleep biology.

A central operating requirement of the PGAs is that information and reagents
generated as part of the program will be made immediately and freely available
to the research community.  This will accelerate hypothesis-driven studies by
providing biologically validated animal models and
sequence/expression/function related information to the NHLBI research
community.  The establishment of education programs by the PGAs is an
additional benefit to the scientific community.  The generation and
interpretation of data from the PGAs will enable a broad range of
investigators to exploit the unique opportunities provided by the information
coming from the HGP and related technologies.  The cross-disciplinary nature
of the PGAs will bring investigators from varying disciplines and unique
perspectives to the investigation of heart, lung, and blood disorders.  It is
anticipated that the relevant expertise needed to distill the information from
the HGP (e.g., expertise in the relevant biology, informatics, molecular
biology, clinical medicine, genomics, etc.) will not necessarily reside in the
same geographical area.  Therefore, the concept is to enable investigators at
different locations to design a PGA as easily as investigators at a single
location.  In addition, the NHLBI will facilitate and encourage interaction
between the individual PGAs.

Research Scope

The Human Genome Project has begun to identify the 50,000 -100,000 human
genes, of which only a small fraction are presently associated with a
function.  Roughly 6,000 human genes in GenBank have an associated phenotype. 
The major objectives of the PGAs are TO IDENTIFY SUBSETS OF GENES THAT ARE
PARTICULARLY RELEVANT TO THE BIOLOGY, DIAGNOSIS, MANAGEMENT, TREATMENT AND
PREVENTION OF HEART, LUNG, BLOOD AND SLEEP RELATED DISORDERS AND TO PRIORITIZE
INFORMATION FOR FURTHER FOCUSED STUDY.  A variety of function-based approaches
are encouraged, such as generation of model systems through systematic
mutagenesis, generation of model systems by marker-assisted selection,
quantitative analysis of gene expression patterns under a wide variety of
conditions, systematic high-throughput examination of total genetic variation,
and development of high-throughput assays of physiologic function to generate
a link between physiologic function and gene variation.  The assays may target
genes and/or gene products (proteomics).  Functional and pathophysiological
studies can be performed in humans as well as a variety of models including
mouse, rat, and zebrafish.

The SCIENTIFIC THEME(S) of a PGA should be based upon the creativity and
imagination of the applicants and should ADDRESS MAJOR BIOLOGICAL PROCESSES
AND SYSTEMS required for cardiovascular, pulmonary, and hematologic function
(e.g., development, differentiation, inflammation, vascular biology,
hemostatic mechanisms) and dysfunction (e.g., stroke, heart failure,
hypertension, atherosclerosis, arrhythmia, asthma, chronic obstructive
pulmonary disease, pulmonary hypertension, sleep disorders,
hemoglobinopathies, thrombotic disorders).  APPLICATIONS THAT HAVE BROADLY
BASED SCIENTIFIC THEMES OF RELEVANCE TO HEART, LUNG, AND BLOOD DISEASES;
ENCOMPASS MORE THAN ONE TISSUE OR ORGAN SYSTEM; AND ARE HIGHLY INTEGRATED AND
INTERACTIVE WILL BE CONSIDERED THE MOST COMPETITIVE AND WILL RECEIVE SPECIAL
CONSIDERATION BY THE NHLBI.

The PGAs will also have the opportunity to carry out INNOVATIVE RESEARCH by
IMPORTING, INCORPORATING, AND IMPROVING LEADING EDGE TECHNOLOGIES, BY
DEVELOPING ANALYTICAL AND COMPUTATIONAL TOOLS, and by ADDRESSING PHYSIOLOGICAL
AND PATHOPHYSIOLOGICAL QUESTIONS using these technologies and tools.  Although
the incorporation of novel technologies is critical for this program, the
primary focus of a PGA should not be technology development.

While a primary outcomes of the PGAs will be information concerning subsets of
genes (and gene products) relevant to heart, lung, and blood biology, other
valuable reagents may be generated, including valuable animal models, improved
technologies, and novel analytical strategies.  THESE TOOLS, AS WELL AS THE
INFORMATION GENERATED BY THE PGAS, WILL BE MADE AVAILABLE TO THE RESEARCH
COMMUNITY IN A TIMELY MANNER.

Currently, only a small number of heart, lung, and blood investigators are in
a position to use genomic information and technologies.  To address this
deficiency, a requirement of the PGAs will be to ESTABLISH TARGETED TRAINING
AND EDUCATION PROGRAMS.  These programs should incorporate on-site training as
well as formalized workshops to disseminate information and technologies. 
There should be coordination between the PGAs so that training and education
courses are not redundant and do not compete for the same students.

The multi-disciplinary nature of the PGAs will bring together investigators
from varying disciplines in order to effectively accomplish the goals of this
RFA.  It is anticipated that the desired expertise (e.g., in the relevant
biology, informatics, molecular biology, clinical medicine, genomics, etc.)
will not necessarily reside in the same geographical area.  Therefore, the
intent of this program is to enable investigators at DIFFERENT LOCATIONS to
design a PGA as easily as investigators at a single location.  A PGA, however,
will need to pay particular attention to maintaining cohesiveness and
synergism if it is geographically dispersed.

Each PGA must include plans to include all of the above objectives (biology
driven, genome-wide link to function, innovative research, information and
resource dissemination, and education/training).

In summary, the PGAs are an essential next step in providing functional
information about genes on a large scale, as well as technologies, biological
models and reagents, methodologies, and software that will be critical for
individual investigators to understand the biology and pathobiology of heart,
lung, and blood function and disease.  It will make available critical
resources that are difficult or too expensive to develop in most individual
laboratories, and serve as a springboard for the development of future
hypothesis-driven research.  The PGAs will capitalize on the foundation of
basic research and utilize the data and technologies emerging from the Human
Genome Project to greatly accelerate research progress critical for the
development of new and better ways to diagnose, manage, prevent, and treat
heart, lung, and blood diseases.  It is anticipated that a wide range of
benefits to all areas of heart, lung, blood, and sleep research will result
from this concept.  For example, there may be tremendous opportunities to
design clinical and population-based studies that use genomic information to
understand the variability of responses to diet, behavior, and drugs.  We can
expect to develop the knowledge that will enable therapies to be directed to
the underlying molecular pathology, new prevention strategies, improved drug
design, and better ways to diagnose and predict heart, lung, and blood
diseases.

Possible Examples

Several illustrative PGA models are described below.  However, these are
examples only and applicants are encouraged to develop the types or subsets of
data, resources, and biological themes that they believe would be most useful
to the heart, lung, blood, and sleep scientific communities.

1.  Variation Discovery Program

This PGA would focus on the generation of high through-put sequencing of
specific genes of interest in heart, lung, blood, and sleep health and disease
in large numbers of individuals.  These multiple sequence data would provide
information on the total observable variation in genes or regions of interest.

This PGA would consist of several components: one or more groups providing the
epidemiological and population genetics expertise and samples, a group
generating the sequence information, a computational group performing analyses
to determine which variations have functional significance, an informatics
group, and an educational component.  Other groups could be added to provide
additional samples or analyze specific sets of data.

Such a PGA could sequence candidate genes that play a central role in key
physiological functions (e.g., transport, metabolism, receptors and signal
transduction) involved in determining cardiovascular, pulmonary, and
hematological health in humans.  Resources provided to the scientific
community would include high-throughput sequencing technology, DNA sequences,
software, sites of genetic variability and possible combinations of alleles
(haplotypes), and information on populations examined.  However, it is not
expected that the population resource itself would be made available through
this program.

2.  Variable Expression Program

This PGA would identify groups of genes that tend to be expressed together and
their levels of respective expression under a wide range of conditions
involving various physiological and pathophysiological states of interest to
heart, lung, and blood biological systems.  This PGA would consist of several
components: one or more groups providing specialized tissue samples from human
or animal models, a group generating the arrays, an informatics group to track
and compartmentalize the data as well as provide user friendly access to the
data, and an educational component.

A Variable Expression PGA could explore a wide-range of biological issues of
heart, lung, and blood research.  For example, an expression PGA might
identify individual and/or classes of genes differentially expressed during
hematopoietic development or during different stages of cardiac or pulmonary
development, both in normal and pathological states.  This PGA would provide
information on tissue selection technology, expression profile technology,
expression profile data, and bioinformatic tools and technologies to the
scientific community.  Individual investigators could go to the Expression
Assay Database to look at a particular gene or sets of genes to learn how
expression is altered under various conditions, and, conversely, compare
various conditions to learn which genes or gene sets are altered.  Such
information would then be used to develop hypotheses that can be tested in
individual laboratories.

3.  Genome-wide Mutagenesis and Phenotyping Program

This PGA would generate new animal models through genome-wide mutagenesis that
would lead to the identification of new genes or pathways contributing to
disorders affecting the heart, lung, blood, and sleep systems.  In order to
identify new animal models that are the most useful to heart, lung, blood, and
sleep investigators, relevant high through-put phenotyping would be necessary. 
This PGA would consist of several components: a mutagenesis group, one or more
phenotyping groups, an informatics group, and an educational component.

This PGA would provide the scientific community with information on mutation
and phenotyping technology, and provide newly-generated animal models and
their relevant phenotypic data.  For example, a cardiac or pulmonary
physiologist could scan the PGA database for particular phenotypes and then
order animals of interest, study and characterize them, and in some cases, add
new genes of known function to the repertoire of genes affecting cardiac and
pulmonary physiology.

Each of the models listed above provides unique approaches to study the
function of genes responsible for heart, lung, blood and sleep disorders using
a variety of technological strategies.  These are examples only.  Applicants
should not feel limited to the areas mentioned above and are encouraged to
submit any topic pertinent to the objectives of the RFA.  DISCUSSION WITH
INSTITUTE STAFF PRIOR TO FULL DEVELOPMENT OF AN APPLICATION IS HIGHLY
RECOMMENDED.

It is also envisioned that investigators may want to pursue physiological and
pathophysiological questions using a combination of these, or possibly other,
approaches and genomic technologies.  As an example of combining several
approaches and questions, for any given biological theme (e.g., 
revascularization, pulmonary inflammation, cardiac development) there are a
number of candidate genes that could be characterized in a variety of
individuals to find all the observable variation.  In addition, expression
arrays can be developed from various health and disease states in human and
animal models that follow these candidate genes, while new pathways and sets
of genes arising from the expression array data from the various
health/disease states can also be examined.  Furthermore, genome-wide
mutagenesis in animal models could lead to the discovery of new candidate
genes that may be analyzed through the variation discovery process or followed
on expression arrays.

SPECIAL REQUIREMENTS

Organization, Operation, and Oversight

Internal PGA Steering Committee (PSC):
Each PGA will use an Internal PGA Steering Committee to govern its own
activities.  An Internal PGA Steering Committee will be used to achieve
suitable coordination within a PGA, and should be comprised of the PGA
Director, the PIs of its various components (e.g., Informatics Center,
Laboratory Center(s), Data Coordinating Center, Genotyping Center, Sequencing
Center, Education and Training Center, and Animal Model Center), and one NHLBI
representative.  An application must also indicate who would be responsible
for assisting the Program Director with the day-to-day administrative details,
coordination of activities both within and between PGAs, and with the planning
and evaluation of the program.  The Program Director must exercise great
diligence in preserving the interactions of the participants and the
integration of its components in order to maintain cohesiveness and synergism. 
Publication and ancillary study policies should be incorporated in the
operating procedures and agreed to by all awardees.

Inter-Program Governance by a PGA Program Coordinating Committee (PGAP-CC):
A PGA Program Coordinating Committee will be the main governing body of
multi-PGA studies and activities.  Voting membership will consist of two
representatives from each PGA, one of whom must be the Program Director, and
NHLBI Project Scientists.  The Chairperson, who will be someone other than an
NHLBI staff member, will be selected by the PGA Program Coordinating
Committee.  Recommendations regarding all scientific issues will be decided by
majority vote.

As it is responsible for the overall guidance of multi-PGA coordination, the
PGA Program Coordinating Committee will: establish and encourage well focused
collaborations among the different PGAs; develop common protocols and methods
where possible; determine the manner and extent of data and resource sharing;
facilitate the sharing of information, tools, and resources; develop training
and education programs; and plan and evaluate changes in research design and
strategies as developments warrant.  The extent of standardization, uniformity
of data sets, and sharing of data, reagents, and specimens will be determined
on the basis of feasibility and greatest promise from the recommended research
scope of the PGAs awarded.  Those aspects of a PGA that do not involve sharing
and collaboration between PGAs may be pursued independently.

Because of the magnitude and complexity of this program, it is anticipated
that the PGA Program Coordinating Committee will convene subcommittees to
cover specific cross-cutting areas, such as quality control, molecular biology
strategies, phenotypic measurements, genotyping and sequencing, data
collection, data analysis, computation biology, database issues, training and
education, sharing of study data and materials, ethical, legal and social
issues, intellectual property rights, publication policies and procedures, and
the rights to authorship.  Although the PGA Program Coordinating Committee
will develop procedures and assign responsibilities for preparation of
publications resulting from collaboration among programs, this does not
abrogate each PGA's ability to publish its own findings.

Publication and ancillary study policies should be incorporated in the
operating procedures and agreed to by all awardees.  Membership of
subcommittees will be determined by the PGA Program Coordinating Committee and
consist of scientists engaged in the PGAs and others as needed to ensure
appropriate coverage of subject matter and balance.  An NHLBI scientist (or
where necessary, scientists) will serve on subcommittees as deemed appropriate
by the NHLBI.

Willingness to Collaborate:
As described above, representatives of PGA components and the NHLBI Project
Scientists will collaborate to develop common protocols, standard procedures,
and non-redundant education and training efforts.  Hence, prospective PGA
representatives, such as the PIs of the Informatics Center, Laboratory
Center(s), Data Coordinating Center, Genotyping Center, Sequencing Center,
Education and Training Center, and Animal Model Center, must agree to serve on
the Internal PGA Steering Committee, express willingness to collaborate in
multi-PGA studies, and be willing to serve on the PGA Program Coordinating
Committee.

External Scientific Panel (ESP):
An External Scientific Panel, consisting of non-PGA affiliated scientists,
will be appointed by the Director, NHLBI to provide overall advice on
direction, as well as monitoring progress and coordination of the individual
PGAs and the PGA Program organization; the PSCs and PGAP-CC will have the
opportunity to nominate members for this Panel.  However, possible members to
the ESP should not be named in the application.  It is anticipated that the
ESP will meet annually with the PGAP-CC following the submission of the non-
competing applications.

Terms and Conditions of Award

The cooperative agreement is an award instrument establishing an "assistance"
relationship (in contrast to an "acquisition" relationship) between NHLBI and
a recipient, in which substantial NHLBI scientific and/or programmatic
involvement with the recipient is anticipated during performance of the
activity.  The NHLBI goal is to support and/or stimulate the recipient's
activity by involvement in and otherwise facilitating the activity in a
"partner" role, but avoiding a dominant role or prime responsibility. 
Consistent with this concept, the dominant role and prime responsibility
resides with the PI for the project as a whole, although specific tasks and
activities may be shared between the awardee and NHLBI staff as noted below. 
The terms and conditions, below, elaborate on these actions and
responsibilities, and the awardee agrees to these collaborative actions with
the NHLBI Project Scientists toward achieving the project objectives.  It is
anticipated that these terms and conditions will enhance the relationship
between the NHLBI staff and the principal investigator(s), and will facilitate
the successful conduct and completion of the study.  These agreements will be
in addition to, and not in lieu of, the relevant NIH procedures for grants
administration.  The terms will be as follows:

1.  The awardee(s) will have lead responsibilities in all aspects of their
study, including any modification of study design, conduct of the study,
quality control, data analysis and interpretation, preparation of
publications, dissemination of data, tools, and technologies, and
collaboration with other investigators, unless otherwise provided for in these
terms or by action of the PGA Steering Committee or PGA Program Coordinating
Committee.

2.  The NHLBI Project Scientists will serve on the PGA Steering Committee and
the PGA Program Coordinating Committee; he/she or another NHLBI scientist may
serve on other study committees, when appropriate.  The NHLBI Project
Scientist (and the other cited NHLBI scientists) may work with awardees on
issues coming before the Steering or Coordinating Committees and, as
appropriate, other subcommittees, e.g., quality control, database
coordination, educational and training programs, final data analysis and
interpretation, data, tools, and technology dissemination, preparation of
publications, and development of solutions to major problems.

3.  Awardee(s) agree to the governance of the study through a PGA Steering
Committee (PSC).  Each PGA will use an Internal PGA Steering Committee to
govern its own activities.  An Internal PGA Steering Committee will be used to
achieve suitable coordination within a PGA, and should be comprised of the PGA
Director, the PIs of its various components (e.g., Informatics Center,
Laboratory Center(s), Data Coordinating Center, Genotyping Center, Sequencing
Center, Education and Training Center, and Animal Model Center), and one NHLBI
representative.  As components of the PGA may be geographically dispersed, the
PSC should meet 3-4 times per year with monthly conference calls.

4.  Awardee(s) agree to the governance of the study through a PGA Program
Coordinating Committee (PGAP-CC).  A PGA Program Coordinating Committee will
be the main governing body of multi-PGA studies and activities.  Voting
membership will consist of two representatives from each PGA, one of whom must
be the Program Director, and two NHLBI Project Scientists.  The Chairperson,
who will be someone other than an NHLBI staff member, will be selected by the
PGAP-CC.  Recommendations regarding all scientific issues will be decided by
majority vote.  As it is responsible for the overall guidance of multi-PGA
coordination, the PGAP-CC will: establish and encourage well focused
collaborations among the different PGAs; develop common protocols and methods
where possible; determine the manner and extent of data and resource sharing;
facilitate the sharing of information, tools, and resources; develop training
and education programs; and plan and evaluate changes in research design and
strategies as developments warrant.  The extent of standardization, uniformity
of data sets, and sharing of data, reagents, and specimens will be determined
on the basis of feasibility and greatest promise from the recommended research
scope of the PGAs awarded.  Those aspects of a PGA that do not involve sharing
and collaboration between PGAs may be pursued independently.  Because of the
magnitude and complexity of this program, it is anticipated that the PGAP-CC
will convene subcommittees to cover specific cross-cutting areas, such as
quality control, molecular biology strategies, phenotypic measurements,
genotyping and sequencing, data collection, data analysis, computation
biology, database issues, training and education, sharing of study data and
materials, ethical, legal and social issues, intellectual property rights,
publication policies and procedures, and the rights to authorship.  Although
the PGAP-CC will develop procedures and assign responsibilities for
preparation of publications resulting from collaboration among programs, this
does not abrogate each PGA's ability to publish its own findings.  Publication
and ancillary study policies should be incorporated in the operating
procedures and agreed to by all awardees.  Membership of subcommittees will be
determined by the PGAP-CC and consist of scientists engaged in the PGAs and
others as needed to ensure appropriate coverage of subject matter and balance. 
An NHLBI scientist (or where necessary, scientists) will serve on
subcommittees as deemed appropriate by the NHLBI.  The PGAP-CC should meet 4
times in the first year and 2-4 times per year thereafter and have regularly
scheduled conference calls.

5.  An External Scientific Panel (ESP) will be appointed by the Director,
NHLBI to provide overall advice on direction as well as monitoring of progress
and coordination of the individual PGAs and the PGA Program organization; the
PSC and PGAP-CC will have the opportunity to nominate members for this Panel. 
Scientists that serve on this Panel will not be affiliated with any of the
PGAs.  Meetings of the ESP will ordinarily be held annually in Bethesda, MD,
although site visits may be convened as appropriate.  An NHLBI Project
Scientist shall serve as Executive Secretary to the Panel.

6.  Awardees will retain custody of and have primary rights to their data
developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies.  The collaborative
protocol and governance policies will call for the continued timely submission
of data to a public and/or accessible databases; the submittal of copies of
the collaborative data sets to each principal investigator upon completion of
the study; procedures for data analysis, reporting and publication; and
procedures to protect and ensure the privacy of medical and genetic data and
records of individuals.  The NHLBI Project Scientist, on behalf of the NHLBI,
will have the same access, privileges and responsibilities regarding the
collaborative data as the other members of the Steering Committee (i.e.,
cooperative agreement awardees).

7.  Support or other involvement of industry or any other third party in the
study -- e.g., participation by the third party;  involvement of project
resources or citing the name of the project or the NHLBI support; or special
access to project results, data, findings or resources -- may be advantageous
and appropriate.  However, except for licensing of patents or copyrights,
support or involvement of any third party will occur only following
notification of and concurrence by NHLBI.

8.  The awardee(s) are expected to put all study materials and procedure
manuals into the public domain.  Awardees are expected to publish and publicly
disseminate results, data, and other products of the study, concordant with an
NHLBI approved data, technology, and tool release protocol and governance
policies and protocols.  However, during or within three years beyond the end
date of the project period of NHLBI support, unpublished data, unpublished
results, data sets not previously released, or other study materials or
products are to be made available to any third party only with the approval of
the Steering Committee and in accordance with paragraph 6.  Any web site
developed by a PGA for dissemination of information may be linked to the NHLBI
web site.

9.  The NHLBI reserves the right to terminate or curtail the study (or an
individual award) in the event of (a) failure to develop or implement a
mutually agreeable collaborative protocol, (b) substantial shortfall data
reporting and dissemination, quality control, or other major breach of the
protocol, (c) substantive changes in the agreed-upon protocol with which NHLBI
cannot concur, or (d) human subject ethical issues that may dictate a
premature termination.

10.  Any disagreement that may arise in scientific/programmatic matters
(within the scope of the award), between award recipients and the NHLBI may be
brought to arbitration.  An arbitration panel will be composed of four
members--one selected by the PGA Steering Committee (with the NHLBI member not
voting) or by the individual awardee in the event of an individual
disagreement, a second member selected by NHLBI, the third member selected by
the two prior members, and the fourth panelist will be a member of the
National Heart, Lung, and Blood Advisory Committee.  This special arbitration
procedure in no way affects the awardee's right to appeal an adverse action
that is otherwise appealable in accordance with the PHS regulations at 42 CFR
part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of
NHLBI under applicable statutes, regulations and terms of the award.

11.  These special terms of award are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS Grant Administration
Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant
administration policy statements.

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 was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at:
http://grants.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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

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

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

PUBLIC BRIEFING

Prospective applicants are invited to attend a briefing on the PGAs on
November 19, 1999 on the NIH Campus in Bethesda, Maryland.  NHLBI staff will
explain the purpose of the program, provide instructions about the application
process, and answer questions.  Applicant institutions are urged to send a
representative to this briefing, both to gather information and to exchange
ideas with other potential applicants.  Anyone who cannot attend the pre-
application meeting will be provided with any distributed materials and a
summary of the discussion through the NHLBI web site.  For further information
about the meeting, contact the NHLBI Program Staff listed under INQUIRIES.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel
and participating institutions, and the number and title of this RFA. 
Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows Institute staff to estimate the potential review workload and
avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. C. James Scheirer, at the address
listed under INQUIRIES by January 10, 2000.

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 and may be obtained from the Division of
Extramural Outreach and Information Resources,  National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-435-
0714, E-mail: GrantsInfo@nih.gov.  The PHS 398 application kit is also
available on the Internet at http://grants.nih.gov/grants/funding/funding.htm.

The RFA label available in the PHS 398 (rev. 4/98) application form 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.

Additional Material to Include in the Application

To promote development of a collaborative program among the award recipients,
all of the issues discussed below must be addressed in each application. This
material is in addition to the submission of a research plan, as described in
the section entitled Research Scope.

1.  Recognizing that the expertise and technologies in selected critical areas
are not necessarily located at a single institution or even within a
particular region, the PGAs may have components that are situated in different
geographical locations.  PGAs should consist of a small number of clearly
defined components.  While each component will have a specific expertise, they
must be integrated to work towards a common goal.  It is not clear at this
point, which of the many diverse approaches for prioritizing genomic
information will be the most successful.  Therefore, multiple innovative
approaches are encouraged and will be evaluated during the course of the
program.  Each PGA application must describe a steering committee for internal
governance and operations and must clearly outline the proposed administrative
and organizational structure of their PGA, including integration,
collaborative arrangements, and roles for all key investigators from all
Institutions.  All component parts of an application should be submitted
together as a single package.

The PGA Program Director must devote sufficient time to assure successful
operation of the PGA and its interaction with other PGAs and serve as the key
contact point with the NHLBI and other PGAs.  In addition, the PGA Program
Director must be willing to be part of a PGA Program Coordinating Committee
consisting of representatives of each PGA to deal with issues of coordination
and cooperation for database issues, education issues, and to exchange
information.

2.  Applicants must include detailed plans for release of data and sharing of
resources.  If a public database exists, then the PGA data generated must be
deposited there.  For example, SNP detection, EST surveys, and genomic
sequencing data should all be deposited in GenBank.  Each PGA should
disseminate information about the PGA and the educational/training
opportunities provided by that PGA to the general scientific community through
a web site.  PGA websites should also maintain links to relevant public
databases (i.e., GenBank/Entrez).  PGA websites should expend most of their
creativity and resources designing database and software systems for new types
of data (e.g., expression profiling, quantitative phenotypes, physiological
models) for which no public database currently exists.

3.  Applicants must describe how, when, and in what manner information and
materials and technology will be made available to the scientific community. 
It is anticipated that a variety of workshops, courses, and/or seminars could
be implemented.  In addition, to provide service and training to the
scientific community, visits could be arranged for qualified persons having
interest in methods and technologies utilized by the various awardees of the
program.  The methods and procedures for selecting qualified individuals and
the duration and types of service or training should be delineated in the
application.  Applicants must include a plan for sharing of materials and
information dissemination.  This could include specific Internet based
interfaces, newsletters, or information conferences, seminars, or workshops
that may be held in association with relevant scientific society meetings. 
Prior to implementation of the education/training component, overlap and gap
areas will be discussed by the PGA Program Coordinating Committee.

4.  Applicants must include a plan for quality assurance of pre-publication
data that are made available.

Packaging of the PGA Application

Investigators who wish to establish a PGA will submit concurrent,
cross-referenced individual research grant applications together as a package. 
Each PGA component (e.g., Laboratory Center, Genotyping Center, Data
Coordinating Center, Animal Model Center, etc.) will be directed by a
Principal Investigator (PI).  The component application will contain a
detailed description of the role of that component in the PGA and how it
relates to the overall success of the PGA.  In addition, the application
submitted by the PGA Director, who will be responsible for organizing and
maintaining effective integration and interaction, must also include a clear
description (a Master Plan) of the relationship among the various components;
describe plans for collaboration, interaction, communication, and sharing
among investigators in the PGA; and indicate the mechanisms for handling
day-to-day administrative details, program coordination, planning, and
evaluation.  If two or more components are located at the same Institution, a
single application is acceptable, although not mandatory.  A separate award
will be issued to each successful applicant in a PGA.  However, a single
component (award) will not be considered independent.  The PGA Director has
the responsibility of oversight and coordination of all components of the PGA,
whether or not they are at his/her Institution.

Budget and Related Issues

To fully explore the depth and breadth of heart, lung, and blood
pathophysiology, biology, and epidemiology, up to 10 PGAs are proposed for
support.  It is anticipated that to accomplish the goals set forth for the
PGAs (biology driven, genome-wide link to function, innovative research
including technology importation, information and resource dissemination,
education/training, and geographic dispersion) the cost of each PGA could be
up to $3.5 million (total cost) per year (a three percent escalation per year
may be included as long as the $3.5 million per year is not exceeded in any
one budget period), depending upon the scope of the program, in the initial
phase of the program.  The PGAs will be initially funded for four years, with
an additional four years contingent upon successful competitive peer review.

During the course of the project period, it is anticipated that technologies
will improve and the rate of progress and focus of work supported by the
grant(s) may change.  Accordingly, it is expected that the principal
investigators will be allowed adjustments in scientific direction to
accommodate such changes.  During the course of the award period, the
principal investigators will be invited to meet with NHLBI program staff and
an External Advisory Panel in Bethesda, MD to review progress and sharing. 
Budget requests should include travel funds for the principal investigator(s)
to meeting annually in Bethesda, MD.

Applications should present four budget periods of 12 months each.  Applicants
should provide adequate budget justification and all applicable direct and
facilities and administrative costs should be included.  Estimates of staffing
needs, including the PIs, other professional and support staff must be
included.  The minimum level of effort for Program Directors, (and suggested
for Key Investigators, if applicable) is 20 percent each.  Travel costs for
Program Steering Committee meetings and PGA Program Coordinating Committee
meetings, as detailed under the section titled "Organization, Operation and
Oversight" must be budgeted, along with statements indicating willingness to
participate in these meetings.

Multiple applications may be submitted from a single institution.  However,
the Principal Investigator, focus, theme, and technology must be different. 
In the event that more than one application at a single Institution is funded,
the NHLBI will work with those sites to reduce or eliminate redundancy of
work, and structure the most cost effective program.

The award will be subject to administrative review annually.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application should be
sent to Dr. James Scheirer at the listing under INQUIRIES.  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 the application receipt date listed in the
heading of this RFA. If an application is received after that date, it will be
returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The
CSR will not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications must include
an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
for responsiveness by NHLBI.  Incomplete and/or nonresponsive applications
will be returned to the applicant without further review.

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 Division of Extramural  Affairs, NHLBI, in accordance with the review
criteria stated below.  The roster of the initial review group will be
available via the NHLBI home page four to six weeks prior to the review date.

As part of the initial merit review, all applications will receive a written
critique and undergo a review in which only those applications deemed to have
the highest scientific merit will be discussed, assigned a priority score, and
receive a second level review by the National Heart, Lung and Blood Advisory
Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In the
written comments reviewers will be asked to apply the five standard review
criteria (see below) to each of the following components of the program in
order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals:

(1) The overall goals and mission of the program in meeting the major
objectives of this RFA.

(2) The plans for sharing data and for information dissemination; the plans
for establishing an education/training program; and the plans for innovative
research including technology importation and improvement.

The five standard review criteria are:

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

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

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

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

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

The program will also be evaluated with regard to synergy and interaction:

(6) Synergy and interaction: Is the overall synergy of the component parts of
the program apparent?  Is there an expressed willingness to interact both
within and between programs?  Is the infrastructure appropriate to allow and
foster synergy and interaction?

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

o  The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research.

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

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

Voting and Assigning a Priority Score:

Each component application within the program will be individually evaluated
according to the review criteria listed above.  However, the program will be
scored only as a program and a single priority score will be voted for all
recommended component applications of a PGA.

Schedule

Public Briefing Date:             November 19, 1999
Letter of Intent Receipt Date:    January 10, 2000
Application Receipt Date:         March 14, 2000
Peer Review:                      June/July 2000
Council Review:                   September 7-8, 2000
Earliest Anticipated Start Date:  September 30, 2000

AWARD CRITERIA

Factors that will be considered in making awards include: a) the scientific
merit of the proposed program as determined by peer review, the multi
disciplinary nature of the proposed studies, and the quality of meeting the
special requirements stated in this RFA; b) relevance to the overall
programmatic balance and priorities of the NHLBI and sufficient compatibility
of features proposed in the research plan and qualifications of the
investigators to make a collaborative program for genomic applications to
heart, lung and blood research a reasonable likelihood; and c) the
availability of funds.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Susan E. Old, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9150 (MSC 7940)
Bethesda, MD 20892-7940
Telephone:  (301) 435-0477
FAX:  (301) 480-1336
Email: so40y@nih.gov

James Kiley, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10210 (MSC 7952)
Bethesda, MD 20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
Email: kileyj@nih.gov

Peter Savage, M.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8104 (MSC 7938)
Bethesda, MD 20892-7938
Telephone:  (301) 435-0422
FAX:  (301) 480-1864
Email: savagep@nih.gov

Carol Letendre, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10142 (MSC 7950)
Bethesda, MD 20892-7950
Telephone:  (301) 435-0080
FAX:  (301) 480-0867
Email: letendrec@nih.gov

Direct inquiries regarding review matters to:

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr.,Room 7220 (MSC 7924)
Bethesda, MD 20892-7924
Telephone: (301) 435-0266
Fax: (301) 480-3460
Email: js110j@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jane Davis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7174 (MSC 7926)
Bethesda, MD 20892-7926
Telephone: (301) 435-0166
FAX: (301) 480-3310
Email: davisj@gwgate.nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.837.  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
241 and 285) and administered under NIH grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74 and 92. This program is not subject
to the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products. In addition, Public
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood
development services are provided to children. This is consistent with the PHS
mission to protect and advance the physical and mental health of the American
people.


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