DEVELOPMENT OF ANIMAL MODELS OF HIV RELATED LUNG DISEASE

Release Date: February 11, 1999

RFA:  HL-99-012

P.T.

National Heart, Lung, and Blood Institute
National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  March 29, 1999
Application Receipt Date:  April 29, 1999

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

PURPOSE

The objective of this initiative is to stimulate development and validation of
animal models of HIV-related lung disease and animal based research in these
models.  The models are needed to improve our understanding of the basic
pathogenetic mechanisms of disease in the lung and to begin testing new treatment
strategies.  Areas of interest include animal models of the pulmonary
consequences of HIV infections; HIV interactions with opportunistic infections
in the lung; tuberculosis, with an emphasis on latency, reactivation, and
resistance to Mycobacterium tuberculosis; and better animal models of 
Pneumocystis carinii for studying such things as attachment, phagocytosis, and
killing, the role of the epithelial cell in pathogenesis of P. carinii pneumonia,
the life cycle/cell cycle of P. carinii in the lung, and mechanisms of P. carinii
-induced lung injury.  The development of techniques that would allow better
quantification of microbial pathogens and better ways to identify markers of
local immunity in animal models of HIV related lung disease are encouraged. 
Among the disciplines and expertise that may be appropriate for this research
program are the pathogenesis of infections, immunology, lung cell biology,
molecular biology, bacteriology, mycology, virology, genetics, veterinary
medicine, infectious diseases, pathology, pulmonology, and mathematical modeling.

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 Animal Models of
HIV-Related Lung Disease, is related to the priority areas of HIV infection,
immunization and infectious diseases.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No.017-001-00474-0 or Summary Report: 
Stock No. 017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800) or at
http://www.crisny.org/health/us/health7.html

ELIGIBILITY REQUIREMENTS

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 or local governments, and eligible agencies of the
Federal government.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.  All current
policies and requirements that govern the research grant programs of the National
Institutes of Health (NIH) will apply to grants awarded under this RFA.  Awards
under this RFA to foreign institutions will be made only for research of very
unusual merit, need, and promise, and in accordance with PHS policy governing
such awards.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01) mechanism of
support.  Investigators without prior R29 or R01 support are encouraged to apply
for this RFA and to identify their status on the front of the grant application. 
Specific R01 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 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, applicant institutions, reviewers, and
Institute staff.  Although multidisciplinary approaches are encouraged, it is not
the intent of this RFA to solicit applications for large studies encompassing a
variety of individual subprojects, i.e., program projects.  If collaborative
arrangements through subcontracts with other institutions are planned, consult
the program staff listed under INQUIRIES.

For this RFA, funds must be requested in $25,000 direct cost modules and a
maximum of 12 modules ($300,000 direct costs) per year may be requested.  For
applications directed at developing nonhuman primate models only, a maximum of
16 modules ($400,000 direct costs) per year may be requested.  A feature of the
modular grant concept is that no escalation is provided for future years, and all
anticipated expenses for all years of the project must be included within the
number of modules being requested.  Only limited budgetary information will be
required and any budget adjustments made by the Initial Review Group will be in
modules of $25,000.  Instructions for completing the Biographical Sketch have
also been modified.  In addition, Other Support information and the application
Checklist page are not required as part of the initial application.  If there is
a possibility for an award, necessary budget, Other Support and Checklist
information will be requested by NHLBI or NIAID staff following the initial
review.

The APPLICATION PROCEDURES section of this RFA provides specific details of
modifications to standard PHS 398 application kit instructions.  Applicants are
expected to furnish their own estimates of time required to achieve the
objectives of the proposed research project.  Since a variety of approaches would
represent valid responses to this RFA, it is anticipated that there will be a
range of costs among individual grants awarded.  Up to 5 years of support may be
requested on R01 applications.

This RFA is a one-time solicitation.  Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.  It is anticipated
that support for this program will begin in September 1999.  Administrative
adjustments in project period and/or amount may be required at the time of the
award.

Applicants from institutions that have a General Clinical Research Center (GCRC)
funded by the NIH National Center for Research Resources may wish to identify the
GCRC as a resource for conducting the proposed research.  If so, a letter of
agreement from either the GCRC program director or principal investigator should
be included with the application.

The National Institute of Allergy and Infectious Diseases (NIAID) is particularly
interested in developing new animal models of tuberculosis, especially as the
models relate to testing new treatment strategies.  Of primary interest in the
area of tuberculosis are animal models of latency and animal models in which
markers of immunity may be identified and candidate vaccines may be tested.

This RFA is co-sponsored by  NHLBI and NIAID.  Because of the overlapping
interest in the scientific areas included in the RFA, all the applications
submitted in response to it will receive dual assignments (i.e. NHLBI primary
with NIAID secondary or NIAID primary and NHLBI secondary).

FUNDS AVAILABLE

It is anticipated that for fiscal year 1999, approximately $4.0 million, total
costs, will be committed by NHLBI and $0.5 million, total costs, will be
committed by NIAID, specifically to fund applications pertaining to animal models
of tuberculosis, submitted in response to this RFA.  Awards of grants pursuant
to this RFA is contingent upon receipt of such funds for this purpose.  It is
anticipated that approximately 12 new grants will be awarded under this program. 
The specific number to be funded will, however, depend 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 or other necessary
administrative adjustments.  Indirect costs will be awarded based on the
negotiated rates.  Applicants may request up to 5 years of support.

RESEARCH OBJECTIVES

Background

The persisting threat of tuberculosis and other opportunistic infections in the
HIV positive population has spurred the development of basic research and
clinical trials.  There continue to be many obstacles to understanding the
pulmonary immunological responses to HIV infection and host microbial
interactions.  Animal models are needed both to improve our understanding of the
basic virologic, immunologic and pathogenetic mechanisms of HIV related disease
in the lung and to test new treatment strategies.

Objectives and Scope

The purpose of this RFA is to generate and establish the usefulness of new animal
models of HIV related lung disease.  New models are needed to gain information
about HIV infection in the lung, to learn about interactions between HIV and
opportunistic infections and  to test new approaches to treatment, including
vaccines.  There is a need to understand the pulmonary immune response to HIV
infection, how HIV infection and local responses to it predispose to
opportunistic infections, how the opportunistic infections in turn affect the
course of HIV, and how treatment of HIV and the opportunistic infections may
eventually lead to immune reconstitution in the lung.

Tuberculosis (TB) is one of the most important respiratory infections associated
with the HIV epidemic. Conventional TB therapy requires prolonged compliance with
multi-drug regimens that have substantial toxicity.  In addition, new drug
resistant strains are emerging; these are frequently fatal when they occur in the
immunosuppressed host and difficult to treat in the immunocompetent population.
While the etiology of tuberculosis is well understood the nature of the
protective immune response to the causative mycobacteria has not been well
delineated.  Issues regarding latency, reactivation, and resistance to infection
are still poorly understood.

The latency of M. Tuberculosis involves survival and persistence of the organism,
the understanding of which has therapeutic implications.  Latency is particularly
difficult to study in human populations because of the very long time course. The
organism may be dormant for decades.  Improved animal models that focus on how
interactions between M. tuberculosis and cells in the lung affect the initial and
long-term pathogenesis of tuberculosis might be of great benefit in this area of
research.

Requirements for induction of latency; requirements for maintenance of latency;
the impact of differential gene expression might all be examined in animal models
of tuberculosis in the lung.  Interferon gamma and TNF knock out mice have
already proved helpful in learning about the pathogenesis of tuberculosis.  It
appears that Class I MHC cytotoxic mechanisms may be required for protection and
that TNF is necessary for killing of the tubercle bacillus.

Better understanding of entry of mycobacteria into the lung would help in
prevention of infection and understanding the fate of the primary lesion would
provide insight into prevention of dissemination.

There is a great need to define protective immunity critically and to develop
alternative animal models to understand the disease process and to evaluate the
efficacy of new vaccines and other new therapeutic approaches to controlling
tuberculosis in a cost effective way.

Pneumocystis carinii pneumonia is another infection that in spite of prophylactic
regimens and progress in antiretroviral therapy, continues to be a major cause
of morbidity and mortality.  The main problem thwarting studies of this organism
is that it cannot yet be cultured in vitro.  Animal models are required.  Such
models have shown that Pneumocystis carinii attaches to type I alveolar
epithelial cells and possibly to alveolar macrophages.  An extremely important
gap in studies of the pathogenesis of Pneumocystis carinii infection, or any
other infection, is inability  to quantify the various steps in pathogenesis in
vivo.  Techniques need to be developed that will allow quantification in animal
models of attachment, phagocytosis, and killing of microbial pathogens.

Pneumocystis carinii pneumonia and pneumonia caused by any infectious pathogen
represent a constellation of findings characterized by microbial growth and
inflammation in the lung.  Morbidity and mortality in pneumonia are ultimately
related to development of injury and fibrosis of the lung during the course of
the infection.  More needs to be learned about how opportunistic organisms, for
example, Pneumocystis carinii, other fungi (opportunistic and pathogenic) and
bacterial pathogens, such as Mycobacterium tuberculosis, cause disease. 
Mechanisms of both direct toxicity to the lung conferred by the organism, and
mechanisms of injury dependent on the immune/inflammatory response should be
studied in animal models.  The impact of HIV disease on normal responses to these
organisms also needs to be studied in animal models such as the chimpanzee model
or transgenic mice capable of expressing CD4 and  co-receptors for HIV entry. 
The explosion of research on HIV co-receptors and chemokines should open up
possibilities for developing new types of animal models.  Mechanisms of toxicity
to the lung caused by infection with Pneumocystis carinii and other fungi,
Mycobacterium tuberculosis, and other bacteria, need to be studied in healthy
animals and in animal models of HIV disease.

Some examples of areas of research that might be included under this RFA are as
follows:

o  Development and validation of animal models of pulmonary immunity in HIV
infection in which to study how HIV alters the normal immune responses of the
lung, how this predisposes to opportunistic infections in the lung, and how the
presence of the opportunistic infection (or treatment of it) affects the course
of HIV disease;

o  Development of animal models of different stages of HIV infection in the lung
to determine the extent to which it is possible to restore pulmonary immune
defenses once they are damaged;

o  Development and validation of new genetically manipulated (e.g. transgenic,
knock out) or immunodeficient animals in which to study the pathogenesis of
pulmonary tuberculosis, and the factors that contribute to innate resistance to
Mtb in the lung and latency;

o  Development and validation of new animal models in which to identify markers
of immunity to pulmonary tuberculosis that could be used in determining the
efficacy of candidate vaccines;

o  Development and validation of new animal models of HIV infection, with altered
chemokines or chemokine receptors to address mechanisms relevant to the
pathogenesis of retroviral infection in the lung and/or opportunistic infections
of the lung;

o  Development and validation of new animal models in which to study bacterial
and fungal lung disease (not P. carinii) associated with HIV infection;

o  Development of new and/or improved animal models of P. carinii pneumonia in
which transmission, pathogenesis, markers of immunity, treatment and prevention
can be studied.

These are examples only.  Investigators should not feel limited to the subjects
mentioned above and are encouraged to submit other topics pertinent to the
objectives of the RFA.  It is anticipated that some projects may include in vitro
comparisons with human or animal cells and tissues, or employ theoretical models,
however, the main emphasis of the application must be on the development and
validation of an animal model.  The initiative is relevant to African American
and Hispanic minority populations who are disproportionately affected by HIV in
comparison to the total population.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI together with NIAID will sponsor
periodic meetings to encourage exchange of information among investigators who
participate in this program.  In the budget of the grant application, travel
funds for a one day meeting each year, most likely to be held in Bethesda,
Maryland, should be included in the modules.  Applicants should also include a
statement in their applications indicating their willingness to participate in
these meetings.

Applications must propose to develop and establish the usefulness of new animal
models of HIV related lung diseases and to the extent possible include hypothesis
driven studies in these new models.  It is acceptable to adapt and validate an
existing animal model, not previously used for this purpose, to study HIV related
lung disease.  The animal models must be relevant to understanding mechanisms of
HIV infection in the lung or HIV-associated lung diseases and the investigators
must provide a strong rationale for the relevance of the animal model to disease
in the human host.  Animal models based on genetic manipulations (e.g. transgenic
and knock out animals) are of particular interest.  Applications that focus on
genetics and molecular mechanisms of HIV related lung disease are encouraged. 
Multidisciplinary approaches to generating the animal new models that include
mathematical modeling are encouraged.  Although the main emphasis of the RFA is
the development and validation of new animal models, some limited comparisons
using human and animal cells and tissues may be appropriate as a component of an
application.  Large clinical studies are not within the scope of this RFA.

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 follow 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), and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994.  The Guidelines are also available at
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

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

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

LETTER OF INTENT

Prospective applicants are asked to submit, by March 29, 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 subsequent
applications, 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 faxed or sent to Dr. C. James Scheirer, at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  Application kits 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 20898-7910, telephone 301-435-0714, Email:
GrantsInfo@nih.gov and on the internet at http://grants.nih.gov/grants/forms.htm

The RFA label found in the PHS 398 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.

This RFA is restricted to R01 grants.  All grants will be awarded as modular
grants.  The modular grant concept establishes specific modules (increments) in
which direct costs may be requested and a maximum level for requested direct
cost.  Only limited budgetary information is required in the application; a
detailed budget need not be provided.

Sample budgets and justification page will be provided upon request, from Mr.
Raymond Zimmerman at the address listed under INQUIRIES or following the
submission of a letter of intent.

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:

o  FACE PAGE - As a reminder, Item 7 should be completed to indicate Modular
Direct Costs requested and Item 8 should reflect Total Costs (Modular Direct plus
F&A costs).

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page DD
of the PHS 398 (rev 4/98).  It is not required nor will it be accepted at the
time of application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget tables on Form page EE of the PHS 398 (rev. 4/98). Only the
requested total direct costs line for each year must be completed based on the
number of $25,000 modules being requested.  Applicants may not request a change
in the amount of each module.  A maximum of twelve modules ($300,000 direct
costs) per year may be requested, with the exception that for applications
directed at developing nonhuman primate models only, a maximum of 16 modules
($400,000 direct costs) per year may be requested, and each applicant may request
up to FIVE years of support for this RFA.  Direct cost budgets will remain
constant throughout the life of the project (i.e., the same number of modules
requested for all budget periods).  Any necessary escalation should be considered
when determining the number of modules to be requested.  However, in the event
that the number of modules requested must change in any future year due to the
nature of the research proposed, appropriate justification must be provided. 
Total Direct Costs for the Entire Proposed Project Period should be shown in the
box provided.

o  BUDGET JUSTIFICATION

-  Budget justifications should be provided under "Justifications" on Form Page
EE of the PHS 398.

-  List the names, role on the project and proposed percent effort for all
project personnel (salaried or unsalaried) and provide a narrative justification
for each person based on his/her role on the project.  UNDER THE JUSTIFICATION
FOR THE PRINCIPAL INVESTIGATOR, INDICATE IF YOU ARE A NEW INVESTIGATOR (I.E. AN
INVESTIGATOR WITHOUT PRIOR R29 OR R01 SUPPORT).

-  Identify all consultants by name and organizational affiliation and describe
the services to be performed.

-  Provide a general narrative justification for individual categories
(equipment, supplies, etc.) required to complete the work proposed.  More
detailed justifications should be provided for high cost items.  Any large
one-time purchases, such as large equipment requests, must be accommodated within
these limits.  No specific costs for items or categories should be shown.

o  CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts are involved
that require transfer of funds from the grantee to other institutions, it is
necessary to establish formal subcontract agreements with each collaborating
institution.  A letter of intent from each collaborating institution should be
submitted with the application.  Only the percentage of the
consortium/contractual TOTAL COSTS (direct and indirect) relative to the total
DIRECT COSTS of the overall project needs to be stated at this time. The
following example should be used to indicate the percentage cost of the
consortium, "The consortium agreement represents 27% of overall $175,000 direct
costs requested in the first year."  A budget justification for the consortium
should be provided as described in the "Budget Justification" section above (no
Form Page 5 required for the consortium).  Please indicate whether the consortium
will be in place for the entire project period and identify any future year
changes in the percentage relative to the parent grant.

If there is a possibility for an award, the applicant will be requested to
identify actual direct and indirect costs for all years of the consortium. Please
note that total subcontract costs need not be calculated in $25,000 modules. 
However, when subcontract funds are added to the parent grant budget, the total
direct cost amount must be included in the number of $25,000 modules requested.

o  BIOGRAPHICAL SKETCH - A biographical sketch is required for all key personnel,
following the modified instructions below.  Do not exceed the two-page limit for
each person.

-  Complete the education block at the top of the form page;

-  List current position(s) and those previous positions directly relevant to the
application;

-  List selected peer-reviewed publications directly relevant to the proposed
project, with full citation;

-  The applicant has the option to provide information on research projects
completed and/or research grants participated in during the last five years that
are relevant to the proposed project.

o  OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page GG). 
Selected other support information relevant to the proposed research may be
included in the Biographical Sketch as indicated above. Complete Other Support
information will be requested by NHLBI or NIAID staff if there is a possibility
for an award.

o  CHECKLIST - No "Checklist" page is required as part of the initial
application.  A completed Checklist will be requested by NHLBI or NIAID staff if
there is a possibility for an award.

o  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.

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 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 must be sent
to Dr. C. James Scheirer at the listed under INQUIRIES.

Applications must be received by April 29, 1999.  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

Applications will be reviewed for completeness by the CSR and for responsiveness
by 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 NIH peer
review procedures.  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 of the applications under review
(usually two to three times the number of applications that the NHLBI and NIAID
anticipate being able to fund under the program) will be discussed, assigned a
priority score, and receive a second level review by the National Heart, Lung,
and Blood Advisory Council or the National Institute of Allergy and Infectious
Diseases Advisory Council.

The personnel category will be reviewed for appropriate staffing based on the
requested percent effort and justification provided.  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.

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, weighting
them as appropriate for each application.  Note that the application does not
need to be strong in all categories to be judged likely to have major scientific
impact and thus deserve a high priority score.  For example, an investigator may
propose to carry out important work that by its nature is not innovative but is
essential to move a field forward.

(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 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?

In addition, the adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the research
will be reviewed.  Plans for the recruitment and retention of subjects will also
be evaluated.

The initial review group will also examine the provisions for the protection of
human and animal subjects, the safety of the research environment, and
conformance with the NIH Guidelines for the Inclusion of Women and Minorities as
Subjects in Clinical Research.

The roster of the initial review group will be available, via the NHLBI homepage.

Schedule

Letter of Intent Receipt Date:  March 29, 1999
Application Receipt Date:       April 29, 1999
Council Review:                 September/October 1999
Anticipated Start Date:         September 29, 1999

AWARD CRITERIA

The following will be considered in making funding decisions: quality of the
proposed project as determined by peer review, availability of funds, and program
priority.  Applications from new investigators will be strongly considered.

The anticipated date of award is September 29, 1999

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:

Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
Email:  peavyh@gwgate.nhlbi.nih.gov

Ann M. Ginsberg, M.D., Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3B06
Bethesda, MD  20892-7630
Telephone:  (301) 496-5305
FAX:  (301) 496-8030
Email:  aginsberg@mercury.niaid.nih.gov

Direct inquiries regarding fiscal matters (e.g. sample budget pages) to:

Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7154, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  zimmermr@gwgate.nhlbi.nih.gov

Inquires regarding review, letters of intent and two copies of the grant
application are to be directed 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: js110j@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance, Nos.
93.838 and 93.361.  Awards are made under authorization of the Public Health
Service Act, Sec. 301 (c), Title IV, Part A (Public Law 78-410, amended by Public
Law 99-158, 42 U.S.C. 241 and 285) for NHLBI and, and administered under PHS
grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 for NHLBI
and 24 CFR 52 and 45 CFR Part 74 for NIAID. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or a 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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