Full Text HL-93-12


NIH GUIDE, Volume 21, Number 44, December 11, 1992

RFA:  HL-93-12L

P.T. 34

  Pulmonary Diseases 
  Infectious Diseases/Agents 
  Biology, Cellular 

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  February 15, 1993
Application Receipt Date:  April 13, 1993


The National Heart, Lung and Blood Institute (NHLBI) invites grant
applications for support of research on the expression of tuberculosis
(TB) in the lung.  The primary objectives of this grant program are to
encourage research on elucidating the factors involved in disease
expression following infection by Mycobacterium tuberculosis (Mtb) and
to determine the mechanisms by which such factors exert their influence
on the lung.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Expression of Tuberculosis in the Lung, is
related to the priority areas of HIV infection, and immunization and
infectious diseases.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).


Among the disciplines and expertise that may be appropriate for this
research program are cell biology, immunology, infectious diseases,
microbiology, molecular biology, molecular immunology, pathology,
genetics, and pulmonary medicine.

Applications may be submitted by 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 Independent Research Support and transition
(FIRST) (R29) award.  Applications from minority individuals and women
are encouraged.

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 announcement 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.


The support mechanisms for this program will be the individual research
grant (R01) and the FIRST award (R29).  While multidisciplinary
approaches are encouraged, it is not the intent of this announcement 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 below.

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

Applicants (who will plan and execute their own research programs) are
expected to furnish their own estimates of time required to achieve the
objectives of the proposed research project.  Up to five years of
support may be requested for R01s; five years are required for FIRST
awards.  Requested budgets for FIRST awards may not exceed those
specified in the FIRST award guidelines.

At the end of the initial award period, renewal applications may be
submitted for peer review and competition for support through the
regular grant program of the NIH.  It is anticipated that support for
this program will begin in September 1993.  Administrative adjustments
in project period and/or amount may be required at the time of the
award.  Since a variety of approaches would represent valid responses
to this announcement, it is anticipated that there will be a range of
costs among individual grants awarded.  This RFA is a one-time
solicitation.  Future unsolicited competing continuation applications
will compete with all investigator-initiated applications and will be
reviewed according to the customary NIH peer review procedures.


Although approximately $1,500,000 for this program is included in the
financial plans for fiscal year 1993, award of grants pursuant to this
RFA is contingent upon receipt of funds for this purpose.  It is
anticipated that six to eight 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 the availability of



The Centers for Disease Control estimates that since 1984 nearly 39,000
excess cases of TB have accumulated in the United States.  This recent
change in the TB morbidity trend appears attributable, in large part,
to TB occurring in persons infected with the Human Immunodeficiency
Virus (HIV), although increasing homelessness and immigration from
regions of the world where TB is endemic are also contributing factors.

Currently a number of general approaches are being actively pursued in
basic research related to TB.  Efforts are ongoing to define
mycobacterial antigens involved in T-lymphocyte-dependent protective
immunity.  Gamma-delta-T-cells appear to be important in the
immunologic response to Mtb and are under vigorous investigation.
Research is being pursued in studies of the immunology of TB in the
context of mammalian heat shock proteins; to date four such proteins
have been identified.

The lung is the portal of entry for Mtb and local defenses in the lung,
including the mucociliary clearance mechanisms and bronchus-associated
lymphoid tissue (BALT), are involved in processes that limit spread of
infection within the lung as well as to extrapulmonary sites.  However,
most current research on TB delves into the systemic immune response to
mycobacteria and basic mycobacteriology.  By contrast, there is little
research on specific pulmonary defenses or on TB as a disease of the

Almost nothing is known about the basic mechanisms of protective
immunity against Mtb in the lung and the local factors that contribute
to lung injury, damage, or fibrosis.  Furthermore, little is known
about the breakdown of the lung defenses that allow the rapid
progression and unusual, extrapulmonary patterns of primary and
reactivation TB that are now being observed in HIV-infected patients
who have depressed immune function.  Little or no effort has been
directed at the molecular and cellular mechanisms of TB, disease
expression in the lung or the events that relate to host defenses in
the human lung.  Beyond descriptive clinical information on the
pathology of TB, almost no new information has been obtained on the
basic mechanisms of protective immunity and the immune factors that
contribute to the natural history of Mtb infection.  A number of
factors are thought to influence susceptibility, resistance, and
severity of disease when the lung responds to infection with Mtb.  Data
from clinical studies suggest a role for innate factors which might
include such things as age, gender, ethnicity, and acquired conditions
such as associated disease states.  Aside from identifying such
factors, there has been no recent progress on obtaining information
about the mechanisms by which they exert their influence on
susceptibility/resistance or severity of TB disease.

Objectives and Scope

The overall objective of this initiative is to encourage research
directed at gaining a better understanding of disease expression in the
lung following infection with Mtb.  Applications are invited for
innovative multidisciplinary approaches to identify the factors
involved in disease expression, to determine their relationship to
other factors of disease, and to better understand how such factors
exert their influence on pathogenesis.

Several topics relevant to the objectives of this RFA are described
below in order to provide a perspective of the scope of the research
that would meet the goals of the program.  Studies in humans are
encouraged where possible.  Investigators are also encouraged to
consider other approaches that meet the goals of this program in
addition to those cited below.

More information is clearly needed to clarify the specific and
non-specific host defenses against Mtb in the lung, the local anatomic
and immunologic factors that influence the natural history of pulmonary
infection, with particular emphasis on the molecular basis for the
generation of immunopathology.  Acquired resistance to TB following
primary infection is known to directly involve the immune system such
that the ability of activated macrophages to ingest and kill virulent
Mtb organisms is influenced by the function and number of T-helper
lymphocytes.  This is of particular interest in the context of HIV
infection where T-helper cells are known to be adversely affected, and
where the pathogenesis of TB in HIV-infected patients has been observed
to differ from the classic granulomatous processes seen in HIV-negative
individuals.  Research directed at obtaining more detail about the
mechanisms of TB pathogenesis and the factors affecting
susceptibility/resistance and severity in the presence of HIV infection
are of particular interest in response to this initiative.

Another area that deserves further study concerns the genetically
determined and acquired local and systemic factors that affect immunity
and disease expression in the lung.  Studies in inbred mice have
revealed a genetic locus that modulates the innate resistance to
mycobacterial infection.  There appears to be a human homolog to this
non-Major Histocompatibility locus.  Various studies have suggested an
association between HLA-type and pulmonary TB.  Epidemiology and
clinical/pathologic studies have indicated that certain racial groups
such as African Americans develop more extensive lung damage from
pulmonary TB.  Basic research that addresses these aspects of TB could
be considered in responding to this initiative.

Little is known about the mechanisms of reactivation of TB in the lung.
The development of animal models that simulate reactivation disease
would permit exploration of areas of research on reactivation that are
not easily addressed in human studies.  Studies in humans that provide
insights into the basic mechanisms of this aspect of disease expression
would also be a desirable approach.

Local factors in the lung such as underlying bronchiectasis or
silicosis are known to influence fibrosis and other sequelae of TB.  In
cases where extensive fibrosis occurs, the mechanisms involved remain
unexplored.  In most cases of TB extensive fibrosis is not seen, yet
when bronchiectasis is present fibrosis is a common occurrence.
Studies elucidating the relationship between TB complicated by
bronchiectasis and/or silicosis, and fibrosis is another example of
research that would meet the goals of this program.


Applications that propose descriptive studies in humans only and do not
contain studies directed at uncovering mechanisms of disease or
supporting hypotheses related to mechanisms of disease expression will
not be acceptable.  This program will not support studies directed at
development of animal models alone.  Models must be applied to the
study of disease mechanisms associated with expression of TB in the
lung and whenever possible, the testing of hypothesis in the animal
model should carry over to human studies. Applications that focus on
molecular biology and molecular immunology of disease expression are of
particular interest.



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and women
in study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to apply
to males and females of all ages.  If women or minorities are excluded
or inadequately represented in clinical research, particularly in
proposed population-based studies, a clear compelling rationale should
be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of the
study.  This information should be included in the form PHS-398 in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.  Applicants are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans [including American Indians or Alaskan Natives],
Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for studies
on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are not subject to these
policies.  However, every effort should be made to include human
tissues from women and racial/ethnic minorities when it is important to
apply the results of the study broadly, and this should be addressed by

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design in inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.  NIH funding
components will not award grants or cooperative agreements that do not
comply with these policies.


Prospective applicants are asked to submit, by February 15, 1993, a
letter of intent that includesa descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the names of any other participating institutions or
investigators, and the number and title of the RFA in response to which
the application may be submitted.  A letter of intent is not binding,
will not enter into the review of any application subsequently
submitted, and is not a requirement for application.  Such letters are
requested for the purpose of obtaining an indication of the number of
applications to be received.  The NHLBI will not provide a response to
a letter of intent.  The letter is to be received no later than
February 15, 1993 and sent to:

Chief, Centers and Special Projects Review Section
Review Branch, Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 496-7351
FAX:  (301) 402-1660


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of Health,
5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
301-496-7441; and from the NIH program administrator named below.  Use
the conventional format for research project grant applications and
ensure the points identified in the section Review Procedures and
Criteria are fulfilled.  To identify the application as a response to
this RFA, check "yes" on item 2a of page 1 of the application and enter
the title, Expression of Tuberculosis in the Lung, HL-93-12L.

The RFA label available in the application kit must be affixed to the
bottom of the face page of the original completed 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.

Send or deliver the completed application and three signed and
completed photocopies to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to the Chief, Centers and
Special Projects Review Section at the address listed under letter of
intent.  It is important to send these two copies at the same time as
the original and three copies are sent to the Division of Research
Grants (DRG).  Otherwise the NHLBI cannot guarantee that the
application will be reviewed in competition for this RFA.

Applications must be received by April 13, 1993.  If an application is
received after this date, it will be returned to the applicant without
review.  The DRG will not accept any application in response to this
announcement that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.
The DRG 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


Upon receipt, applications will be reviewed for completeness by the DRG
and responsiveness to the objectives of this RFA by the NHLBI.
Incomplete applications will be returned withoug further consideration.
If an application is judged unresponsive, the applicant will be
contacted and given an opportunity to withdraw the application or to
have it considered for the regular, investigator-initiated grant
program of the NIH.

Applications judged to be responsive will be reviewed for scientific
and technical merit by an initial review group, convened by the
Division of Extramural Affairs, NHLBI, solely to review these

This initial review will include a preliminary evaluation to determine
scientific merit relative to the other applications received in
response to this RFA (triage); the NIH will withdraw from further
consideration applications judged to be noncompetitive and promptly
notify the principal investigator and the official signing for the
applicant organization.  Those applications judged to be competitive
will be further evaluated for scientific/technical merit by the usual
peer review procedures.

Review Criteria.  The factors to be considered in the evaluation of
scientific merit of each application will be similar to those used in
the review of traditional research project grant applications including
the novelty, originality, and feasibility of the approach; the
training, experience, and research competence of the investigator(s);
the adequacy of the experimental design; the suitability of the
facilities; and the appropriateness of the requested budget to the work


The anticipated date of award is September 30, 1993.  In addition to
the scientific merit of the applications, awards will be based on
responsiveness to the RFA and the availability of resources.


Direct inquiries regarding programmatic issues to:

Hannah H. Peavy, M.D.
Interstitial Lung Diseases Branch
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A09
Bethesda, MD  20892
Telephone:  (301) 496-7034
FAX:  (301) 496-9886

Direct inquiries regarding review matters to:

Chief, Centers and Special Projects Review Section
Review Branch, Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 496-7351
FAX:  (301) 402-1660

Direct inquiries regarding fiscal matters to:

Raymond L. Zimmerman
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A17
Bethesda, MD  20892
Telephone:  (301) 496-4970
FAX:  (301) 402-1200


This program is described in the Catalog of Federal Domestic
Assistance, No. 93.838.  Grants will be awarded under the authority of
the Public Health Service Act, Title III, Section 301 (Public Law
78-410, as amended: 42 USC 241) and 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 to review by a Health Systems


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