DEVELOPMENT OF MOUSE PHENOTYPIC SCREENS FOR HEART, LUNG, AND BLOOD DISEASES

Release Date:  April 13, 1999

RFA:  HL-99-010

P.T.

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  August 1, 1999
Application Receipt Date:  September 15, 1999

THIS RFA USE THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites research grant
applications for the development of phenotypic screening methods in the mouse for
heart, lung, and blood diseases and sleep disorders.  The purpose of this
initiative is to stimulate research on the phenotypic screening of mice for
heart, lung, blood and sleep disorders in order to accelerate the pace at which
mice with heritable disorders that are models of human disease produced through
either targeted or random mutagenesis are made available to the research
community for further investigation or application.  This Request for
Applications (RFA) will support investigators to (1) develop mouse screening and
phenotype characterization protocols, particularly those that can be used for
high throughput analysis of mouse phenotypes; (2) provide for the systematic
validation of these screening protocols against normal inbred mouse strains and
genetically altered mouse strains that approximate the disease of interest; and
(3) provide for the timely dissemination of information and methodologies to the
scientific community. The initiative is in response to the recommendations from
the meeting on "Priority Setting for Mouse Genomics and Genetics Resources" on
the development of phenotyping protocols in the mouse (see NIH Plan for Mouse
Genomics and Genetics Resources at www.nih.gov/science/mouse).

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, Development of Mouse Phenotypic
Screens for Heart, Lung, and Blood Diseases, is related to the priority area of
Heart Disease and Stroke.  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 202-512-1800) or at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic and foreign, for-profit
and non-profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and Local governments, eligible agencies
of the Federal Government, and small businesses.  Applications may represent a
single institution, or may involve several institutions or organizations. 
Applications from minority individuals, women, and persons with disabilities as
principal investigators are strongly encouraged.

Multiple applications from the same institution will not be considered unless
each application is submitted by a different principal investigator, and is
self-contained and independent of others from that institution.  Overlap in the
scientific scope of applications from the same institution will not be accepted. 
This does not preclude cooperation among participants after awards are made.  If
more than one application is envisioned from an institution, the investigators
are encouraged to discuss their plans with the program administrator listed under
INQUIRIES.  Applications submitted in response to this RFA will only be
considered as new applications.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual research
project grant (R01) mechanism of support.  However, specific application
instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME
streamlining efforts being examined by the NIH.  The modular grant concept
establishes specific modules in which direct costs may be requested as well as
a maximum level for requested budgets.  Only limited budgetary information is
required in the application under this approach.  The just-in-time concept allows
applicants to submit certain information only when there is a possibility for an
award.  It is anticipated that these changes will reduce the administrative
burden for the applicants, reviewers, and Institute staff.  Complete and detailed
instructions and information on Modular Grants can be found at
https://grants.nih.gov/grants/funding/modular/modular.htm

Under the modular grant concept, funds must be requested in $25,000 direct cost
modules and a maximum of ten modules ($250,000 direct costs) per year may be
requested for four years.  Any necessary escalation in future years must be
included within the number of modules being requested.  Only limited budget
information will be required and any budget adjustments made by the Initial
Review Group will be in modules of $25,000.  It is anticipated that larger than
normal equipment costs may be incurred in the first year in order to implement
new approaches. As such, applications may exceed the $250,000 direct cost maximum
in the first year by up to 3 modules ($75,000) to cover the cost of new
equipment. The need and cost of equipment must be well justified and must not be
used to cover the cost of equipment already in place or for alteration and
renovations.

The APPLICATION PROCEDURES section of this RFA provides specific details of
modifications to standard PHS 398 application kit instructions.  Application
budgets will be simplified.  Detailed categorical budget information will not be
submitted with the application; budget form pages of the application kits will
not be used.  Instead, total direct costs requested for each year will be
presented.  Information, in narrative form, will be provided only for Personnel
and, when applicable, for Consortium/Contractual Costs.  See section on
application instructions below.

Additional narrative budget justification will be required in the application
only if there is a variation in the number of modules requested.

There will be no routine escalation for future years.  In determining the total
for each budget year, applicants should first consider the direct cost of the
entire project period.  Well-justified modular increments or decrements in the
total direct costs for any year of the project that reflect substantial changes
in expected future activities may be requested.  For example, purchase of major
equipment in the first year may justify a higher overall budget in the first, but
not in succeeding years.

Other Support pages of the PHS 398 will not be submitted with the application.

Information on research projects ongoing or completed during the last three years
of the principal investigator and key personnel will be provided as part of the
"Biographical Sketch."  This information will include the specific aims, overall
goals and responsibilities and should include Federal and non-Federal support.
This information will be used by reviewers in the assessment of each individuals
qualifications for a specific role in the proposed project.

Following peer review, information about Other Research Support will be requested
by NIH from the applicant for applications being considered for award.

Additional budget information will be requested only under special circumstances.

This RFA is a one time solicitation.  Applications for continuation beyond this
initial award period will compete with all investigator-initiated applications
in the regular grant program and according to customary peer review procedures.

FUNDS AVAILABLE

It is anticipated that for fiscal year 2000, total costs of $4,500,000 will be
available for this initiative.  Award of grants pursuant to this RFA is
contingent upon receipt of such funds for this purpose.  Approximately ten new
grants requesting direct costs of up to $250,000 per year for four years are
expected to be awarded under this program.  The specific number of grants to be
funded, however, depends on the merit and scope of the applications received and
on the availability of funds.  Direct costs will be awarded in modules of
$25,000, less any overlap and other administrative adjustments.  The earliest
anticipated award date for successful grant applications is July 1, 2000.

RESEARCH OBJECTIVES

Background

Cardiovascular, pulmonary, and hematologic diseases constitute a large morbidity
and mortality burden on individuals.  In 1996, cardiovascular, lung, and blood
diseases accounted for 1,180,000 deaths, representing 51 percent of all deaths
in the United States.  The purpose of the biomedical research programs supported
by the NHLBI is to contribute to the prevention and treatment of these diseases. 
Because many heart, lung, and blood diseases begin early in life, their detection
and control can reduce the risk of disability and delay death.  The
identification of molecular and genetic factors contributing to the pathogenesis
of cardiopulmonary, blood, and sleep disorders is essential for developing new
preventive and treatment strategies.

Objectives and Scope

The mouse is an excellent model for defining mammalian gene function because mice
exhibit extensive molecular, genetic, immunological, reproductive, physiological,
and pathologic similarities to the human.  Genetic manipulation, integrated with
molecular, cellular, and organ level approaches in the mouse, can facilitate the
investigation of potential pathogenic factors involved in cardiovascular,
pulmonary, and blood syndromes.  With the impending elucidation of the mouse
genome and the availability of techniques to alter the expression and composition
of genes in this species, the mouse offers an excellent model for determining the
functional consequences of gene expression.  Mutations introduced into the genome
can be reflected in functional alterations in physiologic parameters that result
in disorders resembling or modeling human disease.

The systematic classification and characterization of phenotypes is essential for
ultimately mapping the genes responsible for normal and abnormal development and
physiology.  In any search for mutations or altered functional expression,
identification depends on phenotypic screening and its ability to detect
variation from normal. The challenge is to develop efficient, systematic and
comprehensive phenotypic screening procedures and tools that will permit
comparison between laboratories, temporally, and between different strains of
mice.  This is a necessary step before utilizing chemical or other mutagenesis
methods to produce large numbers of mutant mice for the investigation of normal
and abnormal development and physiology.

However, the technology for the functional analysis of genetically altered murine
models has not kept pace with the rapid increase in the production of animals
with mutant phenotypes.  As a result, existing laboratory methods with respect
to heart, lung, and blood measurements are inadequate to measure essential
physiological parameters for screening and characterization purposes.  For
example, while a complete blood count with microscopic differential analysis is
a standard clinical laboratory test that is used for disease diagnosis in humans,
the application of such tests to mice is only now beginning to be utilized on a
regular basis.  The measurement of cardiovascular parameters in mice through
imaging or electrophysiological characterization has been reported, but this
technology is not readily available nor is it amenable to widespread and rapid
screening of large numbers of mice.  Likewise, current  electroencephalographic
methods to monitor sleep are not practical for testing large numbers of
transgenic animals.  Methods available for the measurement of pulmonary function
and disease in the mouse are time consuming and often require manipulations or
challenges over an extended period of time.  This critically limits efforts to
characterize mutant phenotypes and develop models with which to elucidate
molecular pathways and map genes.

Of particular interest to the National Heart, Lung, and Blood Institute are
assays or tools that provide rapid measures of particular molecular parameters
that specify, indicate, or point to dysfunctions or abnormalities in
cardiovascular, pulmonary or hematologic systems.  Thus, a primary focus of this
program is the development of high throughput phenotyping assays or tests that
could efficiently, rapidly, and systematically be used to screen anywhere from
5,000 to 20,000 mice per year for alterations in cardiovascular, pulmonary,
hematologic or sleep physiology.  This could include, but not be limited to,
biochemical surrogate markers, noninvasive imaging modalities, microarray
analysis, or indicator screens.  Another goal is to develop new phenotyping
techniques or methods for heart, lung, blood, and sleep disorders that would
accelerate the emergence of new concepts and improve our understanding of
structural, metabolic, and functional relationships in cardiopulmonary, and blood
systems.

The following are examples of studies that would be responsive to this program:

Develop novel high throughput screening and phenotyping methods which would
identify coagulation and fibrinolytic abnormalities, hemoglobinopathies,
immunodeficiencies, platelet disorders, and bone marrow failure syndromes that
are consequences of protein alterations/deficiencies.

Identify genetic or cellular markers that are the result of dysregulated
expression of genes that play a role in linage commitment, the progression of
differentiation, and hematopoietic self-renewal.

Identify and characterize genetic or cellular components that act as makers for
high blood pressure, atherosclerosis, or cardiac abnormalities.

Develop efficient, reproducible mouse hematology and blood chemistry analysis and
define normal mouse parameters.

Develop challenge assays that would identify increased risk of thrombosis,
asthma, or alterations in the immune response that results from genetic
manipulation.

Develop a screening panel for cytokines associated with increased airway/lung
reactivity.

Develop screening methods which could be used to identify alterations in
pulmonary function, pulmonary arterial pressure, blood gases, and ion channels.

Development of new technologies for screening sleep and wakefulness in the mouse.

Develop a screening panel for factors associated with pulmonary inflammatory
response.

Identify and develop rapid screens for early genetic or cellular markers
predictive of aberrant lung or cardiovascular development or predisposition to
lung or cardiovascular disease

Develop assays that would be predictive of diurnal variations in cardiopulmonary
function, endocrine function, immunological responses, and mechanisms that
regulate sleep such as somnogenic factors.

Develop methods of analyzing altered gene expression for cardiovascular,
pulmonary or hematologic disease by novel technologies, such as DNA or protein
microarray analysis.

SPECIAL REQUIREMENTS FOR THE RFA

In order to be considered responsive to this RFA, applications must propose
studies that focus on the development of screening tools or methods, particularly
high-throughput methods, for characterizing heart, lung, blood or sleep disorders
in the mouse.

Information should be provided on how the proposed new methodologies represent
improvements over currently available methods and the levels of throughput that
can be achieved (number of mice processed per day/week).

Laboratories supported under this program will be required to: 1) Develop and
validate cardiovascular, pulmonary, or hematologic phenotype characterization
protocols, particularly high throughput methods, in the mouse.  The development
of phenotypic characterization protocols needs to provide for the systematic
characterization of the normal physiological parameters of inbred mouse strains
to provide a benchmark against which mutants can be compared.  The validation of
phenotypic screens or protocols must demonstrate the screens or protocols to be
highly reliable and reproducible.  2) Implement  mechanisms to rapidly
disseminate information on phenotypic screening protocols and methodologies to
the scientific community. This may include the development of databases, websites
or detailed training manuals.

PHS policy requires that investigators make unique research resources readily
available to qualified individuals within the scientific community when they have
been published (see PHS Grants Policy Statement in the July 12, 1996 issue of the
NIH Guide to Grants and Contracts).  The dissemination of information and the
sharing of phenotypic methods as they are developed, are critical features of
this program.  Timely sharing of information and methods will enhance scientific
discovery by permitting researchers access to the resources developed under this
program as quickly as possible and is considered essential to stimulate rapid
progress in the development of murine models of disease and avoid unnecessary
duplication of scientific efforts.

In order to ensure the timely sharing of information and materials, applicants
will be requested to describe how, when, and in what manner methods and materials
will be made available to the scientific community.  This might include specific
Internet based interfaces, newsletters, informational conferences, seminars, or
workshops which may be held in association with relevant scientific society
meetings.  It is expected that the resources to be shared include all materials
developed in projects funded under the RFA, including but not limited to, the
following: phenotyping assays and protocols, detailed methods of procedure or
training manuals that provide sufficient detail for scientists in multiple
laboratories to employ the phenotypic methods or assays to phenotypically
characterize animals reliably and reproducibly, and quantitative scores of
reference animals on heart, lung, blood, and sleep disorder phenotyping assays.

It is recognized that time may be required to validate methods or assays, perform
initial analyses, and to protect intellectual property rights to ensure
inventions are pursued and developed rapidly.  Thus, a protected period, from the
time data or materials are developed to the time they are made available to other
qualified investigators, may be appropriate.  The onset and duration of the
period will vary, depending upon the nature of the research project, and
applicants must justify the length of the protected period they specify in the
application.

The initial review group will comment on the proposed plan for sharing of methods
and information dissemination.  The adequacy of the plan will be considered by
NIH staff as part of the criteria for award.  The proposed sharing plan, after
negotiation with the applicant when necessary, will be made a condition of the
award.

There will be an annual meeting of program participants.  Travel funds for a two
day meeting each year, most likely to be held in Bethesda, Maryland, must be
included in the module calculation.  Applicants must include a statement
indicating their willingness to participate in these meetings.

Production of inbred or transgenic mice is not a requirement.  Transgenic mice
already produced in other studies may be used to address the research goals of
this RFA.  Studies in mice must be the principal focus of the application. 
Applicants are encouraged to contact the program officials listed under INQUIRIES
for further information.

RESEARCH INVOLVING HUMAN SUBJECTS

The primary objective of this RFA is to develop phenotypic screening methods in
the mouse for heart, lung, blood and sleep and circadian research.  There may be
instances in which applicants must collect or use pathology specimens derived
from human subjects, or clinical or epidemiological data from projects involving
human subjects. In those instances, the NIH policies described below apply and
must be addressed in the application.

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 research.  This 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
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
28, 1994 (FR 59 14508-14513), in the NIH Guide for Grants and Contracts of March
18, 1994, and is available at the following URL address:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that children (i.e., individuals under the age of 21)
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 Internet address:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by August 1, 1999 a letter of intent
that includes a descriptive title of the proposed research, the name, address,
and telephone number of the Principal Investigator, the identities of other key
personnel and participating institutions, and the number and title of the RFA in
response to which the application may be submitted.  Although a letter of intent
is not required, is not binding, and does not enter into the review of a
subsequent application, the information that it contains allows NHLBI staff to
estimate the potential review workload and to avoid conflict of interest in the
review.

The letter of intent is to be mailed, or faxed, to:

Dr. Ivan Baines
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 6213, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0277
FAX:  (301) 480-3541
Email: bainesi@gwgate.nhlbi.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants, with the modifications noted below.  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
301/710-0267, email: Grantsinfo@nih.gov. Application kits also may be obtained
electronically on the web at  https://grants.nih.gov/grants/forms.htm

The RFA label found 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 (Development
of Mouse Phenotypic Screens for Heart, Lung, and Blood Diseases) and number (HL-
99-010) must be typed on line 2 of the face page of the application form and the
YES box must be marked.

Submit a signed, typewritten original of the application and three signed,
photocopies, making sure that the original application with the RFA label
attached is on top, 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)

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

At the time of submission, two additional copies of the application must be sent
to Review Branch Contact:

Dr. Ivan Baines
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 6213, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0277
FAX:  (301) 480-3541
Email: bainesi@gwgate.nhlbi.nih.gov

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 also 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.

BUDGET INSTRUCTIONS

The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:

FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period.  Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of
the PHS 398.  It is not required and will not be accepted with the application.

BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required and
will not be accepted with the application.

NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page. (See
https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.)  At the
top of the page, enter the total direct costs requested for each year.

Under Personnel, List key project personnel, including their names, percent of
effort, and roles on the project. No individual salary information should be
provided.

For Consortium/Contractual costs, provide an estimate of total costs (direct plus
facilities and administrative) for each year, each rounded to the nearest $1,000. 
List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project.  Indicate whether the collaborating institution is foreign or
domestic.  The total cost for a consortium/ contractual arrangement is included
in the overall requested modular direct cost amount.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall qualifications
of the research team.  A biographical sketch is required for all key personnel,
following the instructions below. No more than three pages may be used for each
person.  A sample biographical sketch may be viewed at:
https://grants.nih.gov/grants/funding/modular/modular.htm

Complete the educational block at the top of the form page;
- List current position(s) and then previous positions;
- List selected peer-reviewed publications, with full citations;
- Provide information, including overall goals and responsibilities, on research
projects ongoing or completed during the last three years.

CHECKLIST - This page should be completed and submitted with the application. 
If the F&A rate agreement has been established, indicate the type of agreement
and the date. It is important to identify all exclusions that were used in the
calculation of the F&A costs for the initial budget period and all future budget
years.

The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by the NHLBI.  Incomplete and/or unresponsive applications will
be returned to the applicant without further consideration.  Applications that
are complete and responsive to the RFA will be evaluated for scientific and
technical merit by an appropriate peer review group convened by the NHLBI in
accordance with the review criteria stated below.  As part of the initial merit
review, a process will be used by the initial review group in which applications
receive a written critique and undergo a process in which only those applications
deemed to have the highest scientific merit, generally the top half of the
applications under review, will be discussed, assigned a priority score, and
receive a second level review by the 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 review, comments on the following aspects of the application will be made
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in the assignment of the overall score.

(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 method? 
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 key personnel?

(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?

Additional Considerations

(1) The development of high throughput phenotyping methods that could be utilized
to screen anywhere from 5,000 to 20,000 mice per year for alterations in
cardiovascular, pulmonary, hematologic or sleep physiology will be given primary
consideration.

(2) Potential of the proposed study to extend existing knowledge about heart,
lung, blood and sleep disorders through the improved characterization of
phenotypes using inbred or transgenic mouse strains.

The personnel category will be reviewed for appropriate staffing based on the
requested percent effort.  The direct costs budget request will be reviewed for
consistency with the proposed methods and specific aims.  Any budgetary
adjustments recommended by the reviewers will be in $25,000 modules.  The
duration of support will be reviewed to determine if it is appropriate to ensure
successful completion of the requested scope of the project.

AWARD CRITERIA

Applicants should be aware that, in addition to scientific merit, program
priorities and program balance, the total costs of the proposed project and the
availability of funds will be considered by NIH staff as well as Advisory Council
in making funding recommendations.  In circumstances in which applications have
similar scientific merit, but vary in cost, NIH is likely to select the more cost
competitive application for funding.

Schedule

Letter of Intent Receipt Date:  August 1, 1999
Application Receipt Date:       September 15, 1999
Date of Initial Review:         February, 2000
Review by Advisory Council:     May, 2000
Anticipated Award Date:         July 1, 2000

INQUIRIES

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

Inquiries regarding programmatic issues to:

John Fakunding, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 9200, MSC-7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-0544
FAX:  (301) 480-1454
Email: jf46f@nih.gov

Mary Ann Berberich, Ph.D.
Division of Lung Diseases
National heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10102, MSC-7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
Email: berberim@gwgate.nhlbi.nih.gov

Rebecca Link, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10178, MSC-7950
Bethesda, MD  20892-7950
Telephone:  (301) 435-0070
FAX:  (301) 480-1046
Email:  linkr@gwgate.nhlbi.nih.gov

Michael J. Twery, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7024, MSC-7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
Email:  Twery@nih.gov

Direct inquiries regarding the receipt and review of applications to:

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  ScheireJ@nih.gov

Direct inquiries regarding fiscal matters to:

Marie Willett
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7156
Bethesda, MD  20892-7926
Telephone:  (301) 435-0144
FAX:  (301) 480-3310
Email: willettm@gwgate.nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.839 and 93.848.  Awards will be made under the authority of the Public Health
Service Act, Section 301 (42 USC 241) and administered under PHS grant policies
and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. 
This program is not subject to the intergovernmental review requirements of
Executive Order 12372 or to 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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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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