Full Text HL-95-013

HIV-ASSOCIATED PATHOGENS OF THE LUNG: LIFE CYCLE REGULATION

NIH GUIDE, Volume 24, Number 1, January 13, 1995

RFA:  HL-95-013

P.T. 34

Keywords: 
  AIDS 
  Pulmonary Diseases 
  Microbiology 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  March 3, 1995
Application Receipt Date:  April 28, 1995

PURPOSE

The purpose of this solicitation is to encourage research on the
molecular basis of cell/life cycle regulation of pathogens and
opportunistic microorganisms that cause lung disease in HIV-infected
hosts.  The request for applications (RFA) focuses on ways in which
the environment in the host lung, including signals from host lung
cells may affect the microbial mechanisms that determine growth and
replication of the microbial agents.  Examples of microorganisms that
would be appropriate for study under this program are Mycobacterium
tuberculosis, Pneumocystis carinii, Histoplasma capsulatum, and
Coccidioides immitis.

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,
HIV-Associated Pathogens of the Lung: Life Cycle Regulation, is
related to the priority area of 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).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit institutions, 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 the First Independent Research
Support and Transition (FIRST) award (R29).  Applications from
minority individuals women and new investigators are encouraged.

All current policies and requirements that govern the research grant
programs of the 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.

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

MECHANISM OF SUPPORT

The support mechanism for this program will be the National
Institutes of Health (NIH) individual research project grant (R01)
and the FIRST award (R29).  While 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.

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.  Because 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.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation 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 1995.  Administrative adjustments in project period and/or
amount may be required at the time of the award.

The National Institute of Allergy and Infectious Diseases (NIAID)
also supports research aimed at a better understanding of the
interactions between the HIV-infected host and a variety of
pathogenic and opportunistic infectious agents.  Therefore,
applications that are of mutual interest are likely to be given a
secondary assignment to NIAID in accordance with the NIH referral
guidelines.

FUNDS AVAILABLE

Although financial plans for fiscal year 1995 include approximately
$2,000,000 for the total cost of the program for the first year,
award of grants pursuant to this RFA is contingent upon receipt of
funds for this purpose.  It is anticipated that no more than eight
awards will be issued 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.

RESEARCH OBJECTIVES

Background

The lung is the portal of entry for a variety of microorganisms many
of which produce disease associated with the HIV epidemic.
Furthermore, the lung is the site of the initial host response to
these invading agents and as such is involved in both specific and
non-specific mechanisms of defense against infection.  In HIV-
infected individuals and other immunocompromised hosts the ability of
invading agents to disseminate systemically appears to be enhanced
due to suppressed cellular immunity.  Many of the organisms that
threaten immunocompromised individuals have complex life/cell cycles
that along with host factors may regulate pathogenic processes in the
lung.  Little is known about the mechanisms by which pathogenic and
opportunistic microorganisms, some of which may have been dormant for
years, become harmful to the host.  For some of these organisms lack
of progress in understanding aspects of their life/cell cycle that
influence pathogenesis can be ascribed to difficulty of in vitro
culture.  For example, the pathogenic Mycobacteria grow very slowly
and methods to maintain sustained growth of Pneumocystis carinii in
vitro are still being sought.

Rapid advances are occurring in understanding the molecular
regulation of the order and timing of eukaryotic cell growth and
division, including signals that limit growth and cause or prevent
cell division.  For example, cyclins acting through cyclic-AMP
dependent protein kinase appear to be an important feature of the
mechanism that integrates cell growth with cell division.  A more
detailed knowledge of the cell cycle indicates that cell replication
appears to depend not just on cell size, but also on the rate of
growth and it has become apparent that it is possible for one
regulatory mechanism to override another, under certain environmental
conditions.

Although investigators have begun to define the homeostatic
mechanisms that integrate cell growth and division in molecular
terms, little is yet known about the enzymatic machinery that might
control the rate and timing of life/cell cycling in many pulmonary
pathogens and opportunistic agents that cause disease in humans.  The
mechanisms whereby host cells and specific forms of these
microorganisms interact in the lung and the extent to which the
intracellular environment of lung cells influence the life/cell cycle
of these microbes are also poorly understood.

Tuberculosis (TB) has reemerged as an urgent health problem in the
United States in the 1980s in conjunction with the HIV epidemic as
well as with other factors such as increased homelessness and
immigration of people from areas where the incidence of TB is high.
An estimated 15 million people in the United States are currently
infected with Mycobacterium tuberculosis (Mtb).  It is expected that
in many of these individuals Mtb will remain dormant, yet a number of
them will develop active disease at some point, most likely through
reactivation of the organisms they harbor.  This is particularly
important because of the ease with which Mtb is communicated and
because of the many individuals who have medical conditions,
especially HIV infection, that increase their risk of developing
active TB.  A variety of host factors, in addition to HIV infection,
put patients at increased risk of TB, presumably by compromising
their immune responses.  However, little is known about the actual
mechanisms that control interactions between the host and Mtb and how
such factors may alter the life cycle of the organism.  Such
knowledge might provide the basis for developing new strategies to
prevent and treat TB.

Pneumoncystis carinii pneumonia (PCP) continues to be an important
complication in individuals infected with HIV.  While the use of a
number of drugs has had an overall suppressive effect on the
incidence of PCP, there remain a number of problems associated with
therapy for this infection.  It is anticipated that a better
understanding of the mechanisms involved in the interaction between
host lung cells and the infectious forms of P. carinii might provide
alternative approaches for treating this opportunistic infection.

Objectives and Scope

The objective of this program is to elucidate the role of life/cell
cycle regulation of a variety of microorganisms that are associated
with the pathogenesis of lung disease, particularly but not
exclusively, in the setting of HIV infection.  These could include
various bacteria, fungi, and protozoa which act as opportunists or as
well-recognized microbial pathogens either alone or in combination
with HIV infection.

Areas of interest under this program include the identification of
markers of microbial replication and the interaction of host and
microbial factors that allow organisms to continue to remain viable
in cells or tissues for many months or years without replicating.  Of
particular interest are the cellular mechanisms responsible for a
change in the relationship between the host cells and the
microorganism that lead to active disease processes in the lung.
Mycobacteria and P. carinii are likely candidates, but studies that
propose to investigate other organisms are also encouraged.  For
example a variety of fungal organisms such as Histoplasma, Candida,
Coccidioides and Aspergillus are also of particular interest.  A
better understanding of the enzymes controlling life/cell cycle
processes might provide insight into the phenomena of microbial
latency and activation/reactivation as well as provide novel targets
for antimicrobial chemotherapy.

The cell division machinery of Mycobacteria, especially Mtb, and the
regulation of microbial division, especially in lung tissue, offer
potential targets for study with respect to pulmonary tuberculosis.
It is thought that the DNA synthetic mechanisms and cell division
apparatus of Mtb are unique.  The genome of Mtb is 70 percent guanine
and cytosine, suggesting that its DNA polymerase has adapted to
handle its more highly stable form of DNA.  The cell division of Mtb
is exceptionally slow for a pathogenic bacterium.  It is unknown
whether this is due to pauses in DNA synthesis, a low constant rate
of DNA synthesis, gaps between DNA synthesis and cell division, or
factors unrelated to DNA replication.  The DNA replication process of
Mtb is thought to be highly error prone which would help explain why
the spontaneous occurrence of resistance to chemotherapeutic agents
is much higher for Mtb than for other microorganisms.  This also
suggests that the DNA polymerase of Mtb may proofread inefficiently
during replication.  The signals that regulate DNA synthesis and the
growth of Mtb, especially in the lung remain to be uncovered.  The
extent to which reactivation may be regulated by DNA replication
processes and whether host cell factors influence these processes are
completely unknown.  While the tubercle bacilli can remain "dormant"
for decades in host cells little is known about the signals that
regulate the transition between active growth and the "dormant"
state.  Projects that are directed toward gaining mechanistic
insights into the processes of reactivation of Mtb, particularly in
the immunocompromised host are of interest.

Projects dealing with fungal infections associated with
immunocompromised hosts would also be responsive.  For example these
might focus on Coccidioides immitis which is characterized by a
sequence which involves inhalation of infectious conidia into the
respiratory tract where they undergo conversion to spherules.  It has
been suggested that leukocytes and carbon dioxide in the lung play a
role in regulating this morphologic change.  Once formed the
spherules undergo a complex series of processes which give rise to
endospores before being distributed locally in the lung or being
disseminated to other organs of the body.  In addition to the
morphologic considerations, a number of other factors are thought to
contribute to the virulence of these organisms.  These include the
antiphagocytic properties of the organism's cell wall, the thickness
and large size of the spherule form of the organism and the large
number of endospores released from each spherule.  The way in which
such processes are signalled and regulated are appropriate topics for
study under this RFA.

In vitro experiments, animal studies and innovative studies using
human cells or tissues, are encouraged.  Research involving humans
should be formulated in the context of mechanistic studies and should
address specific hypotheses.  Large scale clinical studies are beyond
the scope of this RFA.

SPECIAL REQUIREMENTS

Applications that propose descriptive studies and do not contain
hypothesis driven research directed at understanding the mechanisms
underlying cell/life cycles of microorganisms and how these
contribute to the pathogenesis of lung disease will not be
acceptable.  Studies focused exclusively on microorganisms will not
be acceptable; applications must address microbial-host interactions.
Studies directed at understanding how lung cell signals from an
immunocompromised host interact with microbial signals to direct
microbial growth, replication, dormancy and reactivation are of
special interest.  Applications that focus on issues relevant to the
HIV-immunocompromised host and that use molecular approaches are of
particular interest.

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 new
policy results from the NIH Revitalization Act of 1993 (Section 492B
of Public Law 103-43) and supersedes and strengthens the previous
policies (Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

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.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 3, 1995, 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 NIH staff to estimate the potential review
workload and to avoid conflict of interest in the review.  The letter
of intent is to be sent to Dr. C. James Scheirer, at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

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 and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 435-0714.  Use the conventional format for research project
grant applications and ensure the points identified in the section
REVIEW CONSIDERATIONS 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 "HIV-Associated Pathogens of the
Lung: Life Cycle Regulation" HL-95-013.

The RFA label found in form PHS 398 application kit must be affixed
to the bottom of the face page of the original completed application
form PHS 398.  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
photocopies in one package 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, Review
Branch, DEA at the address listed under INQUIRIES.  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 this RFA.

Applications must be received by April 28, 1995.  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 RFA 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness to this RFA by the NHLBI.  Incomplete
applications will be returned without further consideration.  If the
application is not responsive to the RFA, DRG staff may contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.  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 Division of Extramural Affairs, NHLBI in accordance with the
review criteria stated below.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and be
assigned a priority score.  Applications determined to be non-
competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.

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; the appropriateness of the requested
budget to the work proposed; and the adequacy of plans to include
both genders and minorities and their subgroups as appropriate for
the scientific goals of the research.  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 and the safety of the research environment.

AWARD CRITERIA

The anticipated date of award is September 29, 1995.  In addition to
the scientific merit of the applications, awards will be based on
significance to the subject of the RFA and the availability of
resources.

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
Westwood Building, Room 6A09
Bethesda, MD  20892
Telephone:  (301) 594-7425
FAX:  (301) 594-7487
Email:  hpv%nihhwb1.bitnet@cu.nih.gov

Direct inquiries regarding review matters and mail the letter of
intent to:

C. James Scheirer, Ph.D.
Division of Extramural Activities
National Heart, Lung, and Blood Institute
Westwood Building, Room 557
Bethesda, MD  20892
Telephone:  (301) 594-7478
FAX:  (301) 594-7407
Email:  james_scheirer%nihhwb1.bitnet@cu.nih.gov

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) 594-7420
FAX:  (301) 594-7492
Email:  raymond_zimmerman%nihhwb1.bitnet@cu.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.838.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410,
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 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.

The Public Health Service (PHS) 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 American
people.

.

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