Full Text PA-97-084
NIH GUIDE, Volume 26, Number 24, July 25, 1997
PA NUMBER:  PA-97-084


National Institute of Allergy and Infectious Diseases
National Heart, Lung, and Blood Institute
The National Institute of Allergy and Infectious Diseases (NIAID) and
the National Heart, Lung, and Blood Institute (NHLBI), National
Institutes of Health (NIH), invite applications that expand our
knowledge and understanding of the organism Mycobacterium
tuberculosis (M.tb) and its interaction with the human host.
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 PA,
related to the priority areas of Immunization and Infectious
Diseases, and HIV Infection.  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).
 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, and eligible agencies of the Federal government.
Foreign institutions are not eligible for FIRST (R29) awards.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Traditional research project grant (R01) and FIRST (R29) award
applications may be submitted in response to this program
announcement.  Applications for R01 grants may request up to five
years of support; applications for R29 grants must request five years
of support. Responsibility for the planning, direction, and execution
of the proposed research for all applicable mechanisms of support
will be solely that of the applicant.
Although tuberculosis has been a significant cause of human disease
since the 1600s, when it was known in Europe as the "Great White
Plague", and has affected humans since pre-historic times, knowledge
of the pathogenesis of human tuberculosis is still quite sparse.
There are practical reasons for this, including that few laboratories
have the facilities to safely handle the causative pathogen, M.tb,
and that the availability of patient-derived materials for research
purposes is limited.  Additionally, M.tb is a slow-growing organism
that is relatively difficult to manipulate experimentally.  As a
result, many investigators interested in tuberculosis have chosen to
work with model systems and non-pathogenic, more easily investigated,
mycobacteria.  Although much important information has been learned
from these studies, one lesson has been that the unique
characteristics making these organisms easier to work with also
reflect the organisms' inherent differences from M.tb.  It is not
clear how much closer knowledge gained from the perspective of non-
pathogenic mycobacteria will bring us to understanding the
pathogenesis of human tuberculosis, and thus to being able to develop
more effective therapeutic and preventative interventions.
Similarly, information derived from studies in model animal systems
must minimally be verified in infected humans in order to be
applicable to developing improved tools for controlling human
The Tuberculosis Program in the Division of Microbiology and
Infectious Diseases currently supports a wide range of research
activities aimed at improving understanding of tuberculosis, in order
to aid development of more effective diagnostic, therapeutic and
preventative tools for controlling and ultimately eliminating this
disease.  However, due to the practical and experimental difficulties
inherent in studying M.tb, itself, and its interaction with the human
host, the majority of past and current research efforts employ non-
pathogenic mycobacteria and/or model systems rather than human cells
and tissues.  This Announcement is designed to encourage development
of innovative approaches that will facilitate investigations of M.tb,
itself, and its interaction with the human host, allowing for
validation of much of what has been and continues to be learned in
model systems, and increasing our understanding of human tuberculosis
pathogenesis.  The results of such studies should be invaluable in
the development of improved strategies for controlling human
Research Objectives and Scope
NOTE:  Three complementary Program Announcements are being issued:
"The Latent State in Tuberculosis Infection"; "Tuberculosis - Basic
Biology, Immunology and Pathogenesis"; and "Innovative Approaches to
Investigating Human Tuberculosis".
Applications which focus on understanding the latent state in
tuberculosis infection and/or reactivation of tuberculosis should be
submitted in response the PA "The Latent State in Tuberculosis
Infection".  Applications which focus on the use of model systems and
or mycobacterial species other than M.tb to further understanding of
any other aspect of tuberculosis should be submitted in response to
the PA "Tuberculosis - Basic Biology, Immunology and Pathogenesis";
and applications which primarily focus on use of M.tb and/or human
cells, tissues or study populations to study any aspect of human
tuberculosis, per se, other than latency/reactivation should be
submitted in response to the PA "Innovative Approaches to
Investigating Human Tuberculosis".
Many fundamental questions about the biology, biochemistry and
structure of M.tb, its interaction with the human host, and the
mechanisms by which it causes both latent infection and active
tuberculosis remain unanswered. A separate Program Announcement (PA
98- )will address questions associated with the establishment of
latent mycobacterial infections and the development of reactivation
disease, both in humans and in model systems.  Therefore,
applications dealing primarily with these issues will not generally
be considered responsive to this Program Announcement.  This Program
Announcement is meant to encourage applications that specifically
address, in innovative ways, other aspects of M.tb and its
interactions with the human host, including, but not limited to:
o  Developing improved techniques for genetic manipulation of M.tb -
including techniques for mutagenesis and gene transfer,
recombination, and manipulation of mycobacteriophage; and increasing
understanding of M.tb intra- and extracellular replication
o  Developing in vitro and in vivo systems for studying M.tb-human
host interactions via molecular, biochemical and cell biological
approaches, and including early events in infection, events at the
site of infection, mechanisms leading to development of active
disease, and mechanisms leading to development of a protective immune
o  Developing innovative systems and methods for analyzing M.tb
global gene expression - to allow, for example, rapid assessment,
based on whole genome analyses, of the role(s) played by specific
genes in virulence
o  Elucidating M.tb cell wall structure, biosynthesis and function,
especially of nonlaboratory strains (ie, clinical isolates) grown in
o  Understanding determinants of M.tb transmission and identification
of host and pathogen genetic factors that contribute to human
resistance vs. susceptibility to M.tb infection and/or active
tuberculosis disease
o  Developing new tools to elucidate the epidemiology of M.tb
infection, disease and reinfection, and applying new and existing
molecular epidemiologic tools to answer questions of M.tb
transmission and pathogenesis
o  Designing improved therapeutic agents for tuberculosis through
elucidation of mechanisms of drug resistance or activity, including
identification of unique gene products, enzymatic and biochemical
pathways, and structural elements (eg, the cell wall)of M.tb. NOTE:
Applications focused primarily on evaluation and testing of potential
anti-TB drugs and inhibitors appropriate for use in HIV+/TB+
populations will not be considered responsive to this PA, but should
instead be submitted in response to appropriate initiatives issued by
the Division of AIDS, NIAID.
o  Identifying human immune correlates of protection for M.tb
infection and surrogate markers of human disease progression vs.
o  Developing approaches to validation of candidate anti-TB vaccines
in human in vitro systems, and to design of feasible, effective
clinical trials of validated candidate(s)
o  Developing new and improved diagnostic methods (examples of needs
include, especially in developed countries - ability to detect
paucibacillary disease and extrapulmonary disease; especially in low-
income countries - easier and/or more reliable assay than the current
sputum smear assay; in all countries - improved ability to diagnose
TB in HIV+ as well as HIV- patients
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 are
provided that inclusion is inappropriate with respect to the health
of the subjects of the purpose of the research.  This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
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) and the NIH
Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.
Investigators may obtain copies from these sources or from the
program staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
Applications are to be submitted on the grant application for PHS 398
(rev. 5/95) and will be accepted on the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Extramural Outreach and Information,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone (301) 710-0267, email:
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
PA title must also be typed in section 2.
The completed, signed original and five legible, single-sided copies
of the application and any appendices must be sent or delivered to:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
R29 APPLICANTS ONLY.  R29 applications must include at least three
(3) sealed letters of reference attached to the face page of the
original application.  FIRST applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
The NIH Policy Update on Acceptance for Review of Unsolicited
Applications that Request More Than $500,000 Direct Cost for Any One
Year applies to applications in response to this PA.  The Policy
Update was published in the NIH Guide for Grants and Contracts,
Volume 25, No. 14, May 3, 1996, and became effective June 1, 1996.
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 Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
Review Procedures
Applications will be assigned on the basis of established PHS
referral guidelines. Upon receipt, applications will be reviewed for
completeness by the NIH Division of Research Grants.  Incomplete
applications will be returned to the applicant without further
R01 and R29 applications will be reviewed for scientific and
technical merit by study sections of the Division of Research Grants,
NIH, in accordance with the standard NIH peer review procedures. As
part of the initial merit review, all applications will 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
appropriate national advisory council.
Review Criteria
The five criteria to be used in the evaluation of grant applications
are listed below.
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health.  The reviewers will comment on the following aspects of the
application in their written critiques 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 by the reviewers in assigning 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 a 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
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 initial review group will also examine: the appropriateness of
proposed project budget and duration; the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects; the provisions for the
protection of human and animal subjects; and the safety of the
research environment.
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions: quality of the proposed project as
determined by peer review, program balance among research areas of
the announcement, and availability of funds.
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Inquiries regarding programmatic issues may be directed to:
Ann M. Ginsberg, MD, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3B06
6003 Executive Blvd.
Bethesda, MD 20892-7630
Telephone: (301) 496-5305
Fax:       (301) 496-8030
EMAIL:     ag73i@nih.gov
Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Suite 10018, MSC 7952
6701 Rockledge Drive
Bethesda, Maryland 20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
E-mail: hannah_peavy@nih.gov
Direct inquiries regarding fiscal matters to:
Ms. Catherine Walker
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B32
6003 Executive Blvd.
Bethesda, MD  20892-7610
Telephone: (301)402-7146
Fax: (301)480-3780
Email: cwalker@mercury.niaid.nih.gov
Raymond L. Zimmerman
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Suite 7154, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-79??
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
E-mail: raymond_zimmerman@nih.gov
This program is supported under authorization of the Public Health
Service Act, Sec. 301(c), Public Law 78-410, as amended.  The
Catalogue of Federal Domestic Assistance Citations are No. 93.838.
and No. 93.856.
Awards will be administered under PHS grants policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems review.
The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

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