Full Text HL-93-13L


NIH GUIDE, Volume 22, Number 7, February 19, 1993

RFA:  HL-93-13L

P.T. 34

  Pulmonary Diseases 

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  April 5, 1993
Application Receipt Date:  June 10, 1993


The National Heart, Lung, and Blood Institute (NHLBI) invites grant
applications for support of research on non-immune mechanisms of
defense against tuberculosis (TB) in the lung.  The primary
objectives of this special grant program are to identify and
delineate non-immune mechanisms that may be involved in the early
stages of defense against infection and active disease by
Mycobacterium tuberculosis (Mtb) in 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), Non-Immune Defense against 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 biochemistry, cell biology, infectious diseases,
microbiology, molecular biology, pharmacology, pathology, molecular
genetics, and pulmonary medicine.

Applications may be submitted by for-profit or 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.  Foreign institutions
are not eligible for the 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.  R01 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 mechanism for this program will be the individual
research grant (R01) or the First Independent Research Support and
Transition (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.

Applicants from institutions that have a General Clinic 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.  In such a case, a letter of agreement from
either the GCRC program director or principal investigator could be
included with the application.

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 funds.



The lung is the major portal of entry for Mtb and as a result the
cells of the lung are usually the body's first contact with this
pathogen.  It is well established that the immunologic response to
Mtb involves macrophages and lymphocytes is a complex series of
events which are not yet completely understood; this is currently
under vigorous renewed investigation.  While the participation of
components of the immune system is recognized as the major aspect of
defense against mycobacterial infection, there does exist a
substantial lag between the first encounter with the organisms in the
lung and the occurrence of an immune response.  It is of interest to
examine whether a number of mechanisms are operational during the
early stages of infection and are mediated by factors outside the
immune system. It is likely that microorganisms first interact with
lung tissue via adherence molecules or specific receptors. Often this
interaction is facilitated by coating the organisms with opsonic
agents or is inhibited because the organism does not have access to
specific adherence molecules or receptors.  Little is known about
adherence mechanisms of Mtb in the lung.

Although there is a relatively good understanding of the general
principles governing pathogenesis of TB and host defense against Mtb,
there is only rudimentary understanding of the molecular basis of
pathogenesis and host defense. Virtually nothing is known about the
identity of the molecules that may mediate phagocytosis of Mtb, or
about the identity of the molecules that govern selection of the
intracellular pathway of Mtb following phagocytosis. Similarly,
information is lacking about molecules that mediate the organism's
capacity to inhibit phagosome- lysosome fusion or the molecular
mechanisms that allow Mtb to escape microbicidal activity of
macrophages and survive intracellularly.

It has become clear in the past decade that a number of lung cell
products or processes, not usually associated with immune defenses,
have the potential for protecting the lung against foreign substances
by mechanisms that are still incompletely defined and understood.
These include the oxidant/antioxidant system, surfactant and its
components, and molecules such as nitric oxide.  Whether or not these
or other yet unrecognized mechanisms operate in the lung during
infection with Mtb and the degree to which they participate in
defense against Mtb needs to be examined.  This initiative is
intended to encourage such studies.

Objectives and Scope

The overall objective of this initiative is to stimulate research on
non-immune defense mechanisms in the lung following infection with
Mtb.  Applications are invited for innovative multidisciplinary
approaches to elucidate mechanisms which may be part of the lung's
non-immune armamentarium against mycobacteria, especially Mtb.

Several approaches relevant to the objectives of this RFA are
described below to provide a perspective of the scope of the research
that would meet the goals of the program. Studies in humans and
animal models of disease 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.

Activated macrophages are key cells involved in the killing of
microorganisms.  Activation of these cells in the context of the
immune response is achieved by lymphokines.  However, under
conditions that apparently are not directly associated with
involvement of the immune system, alveolar macrophages incubated in a
crude preparation of pulmonary surfactant demonstrate increased
phagocytosis and killing of bacteria. This suggests a non-immune
interaction between surfactant and alveolar macrophages that may have
a role in the clearance of microbes from alveoli.  Recent studies
also suggest that surfactant protein A (SP-A) can modulate macrophage
function.  It is further suggested that this interaction between SP-A
and macrophages is specific and possibly receptor-mediated.  The
macrophage functions thought to be involved in defense mechanisms
modulated by SP-A are phagocytosis, intracellular killing, and
chemotaxis.  It would be important to determine whether SP-A plays a
role in processing mycobacteria, especially Mtb, in the lung, and
what mechanisms related to surfactant and its components contribute
to lung defenses during infection.

Evidence in the past several years has established a role for nitric
oxide as a messenger molecule in white blood cells where it mediates
tumoricidal and bactericidal effects.  Activation of macrophages has
been shown to result in enhanced expression of an inducible nitric
oxide synthase, resulting in the sustained production of large
amounts of nitric oxide.  These activated macrophages then acquire
the ability to kill or injure certain tumor cells, intracellular
parasites, bacteria, and even normal cells. The enhanced nitric oxide
production appears to play a key role in the cytotoxic and cytostatic
ability of macrophages because inhibition of nitric oxide synthesis
eliminates these effects.  Many other cells, including pulmonary
endothelial cells, also contain an inducible form of nitric oxide
synthase and thus are potential candidates for participation in
defense mechanisms in the lung involving this pathway.  Until very
recently, researchers have been unsuccessful in inducing high-output
nitric oxide synthesis from human cells in vitro using a variety of
inducers known to work well with rodent cells.  However, a recent
report has described the induction of high-output nitric oxide
synthesis by human blood monocyte-derived macrophages infected with
Mycobacterium avium.  Investigation of how or if nitric oxide affects
infectivity of Mtb in the lung and which lung cells are involved
would meet the objectives of this program.

Reactive oxygen species are now recognized for their antimicrobial
activity in vitro and have been shown to be capable of participating
in the direct killing of infectious agents.  The balance between
reactive oxygen molecules and their inhibitors is an important factor
to be considered in pathogenetic mechanisms in the lung.  Information
which elucidates the role of oxidant/antioxidant mechanisms in the
lung in response to infection by mycobacteria is also of interest to
this program.

Being underweight has been identified as a risk factor for TB.
Almost nothing is known about the role of the nutritional status of
the host and the underlying metabolic mechanisms which may be
important to natural defense in the lung against Mtb.  Studies
identifying non-immune mechanisms in this area of research would also
be appropriate for inclusion in this program.


Studies involving mycobacterial species other than Mtb may be used to
meet the goals of this program, but these studies must be related to
mechanisms that operate during infection and disease processes
associated with Mtb.  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 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 non-immune disease mechanisms associated
with infection of the lung by mycobacteria and wherever possible, the
testing of hypotheses in the animal model should carry over to human
studies.  Applications that focus on molecular biology and molecular
mechanisms related to the lung's defense against Mtb 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
Section 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 applicants.

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 is 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 April 5, 1993, a letter
of intent that includes a 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, and it 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 of intent is to
be received no later than April 5, 1993 and sent to:

Chief, Centers and Special Projects Review Section
                                       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 of "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 "NON-IMMUNE DEFENSE AGAINST

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.  Otherwise the NHLBI cannot guarantee that the
application will be reviewed in competition for the RFA.

Applications must be received by June 10, 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 critique.


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 without 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 those used in the review
of traditional research project grant applications including,
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 proposed.


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:

Anthony R. Kalica, Ph.D.
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
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
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 grant
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 Agency.


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