Full Text AI-94-009


NIH GUIDE, Volume 22, Number 45, December 17, 1993

RFA:  AI-94-009

P.T. 34

  Biomedical Research, Multidiscipl 

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  February 5, 1994
Application Receipt Date:  March 18, 1994


The Division of Microbiology and Infectious Diseases (DMID) of the
National Institute of Allergy and Infectious Diseases (NIAID) invites
applications for program project (P01) grants to conduct
interdisciplinary research to increase understanding of the biology
and host-pathogen interactions of the medically important fungi.
This fundamental knowledge will be applied to the development of new
and improved strategies for the prevention, diagnosis, and therapy of
the mycoses.


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), Mycology Research Units, is related to the
priority areas 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


Only domestic organizations are eligible to apply for Program Project
(P01) grants.  Applications may be submitted by domestic for-profit
and non-profit organizations, public and private institutions, such
as universities, colleges, hospitals, laboratories, units of State
and local governments, and eligible agencies of the Federal
government.  To achieve the goals of this program project,
subcontract or consortium arrangements are encouraged.  Applications
from minority individuals and women are encouraged.


The mechanism of support will be the Program Project (P01) grant.
This is a mechanism for the support of a broadly based
multidisciplinary research program that has a well-defined central
research focus or objective.  An important feature of the program
project is that the interrelationships of the individual
scientifically meritorious projects will result in a greater
contribution to the overall program goals than if each project were
pursued individually.  The program project grant consists of a
minimum of three interrelated individual research projects that
contribute to the program objective.  The program project grant also
can provide support for certain common resources termed cores.  Such
resources should be utilized by two or more projects within the
program project.

Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total
project period may not exceed five years.  These P01 applications
should not request budgets in excess of $500,000 total direct costs
in the first year and should not request more than four percent
annual inflationary increases for future years.


The estimated total funds (direct and indirect costs) available for
the first year of support for this RFA will be $2.0 million.  In
fiscal year 1995, the NIAID plans to fund approximately three to four
program projects related to this RFA.  This level of support is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  Although this program is provided for in the
financial plans of the NIAID, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.  Funding
beyond the first and subsequent years of the grant will be contingent
upon satisfactory progress during the preceding years and
availability of funds.  At this time, this RFA must be considered as
a one time solicitation.



Fungal infections are being recognized with increasing frequency as
an important cause of both morbidity and mortality in
immunocompromised as well as immunocompetent hosts.  As the use of
immunosuppressive therapies increases in the treatment of patients
with malignant disease or with organ transplants, the frequency of
systemic mycoses undoubtedly will increase.  Current antifungal
therapy is less than optimal, and there is evidence that resistance
to available drugs is developing.  The fungi of medical importance
include, but are not limited to, Aspergillus fumigatus, A. flavus,
Blastomyces dermatitidis, Candida albicans, Coccidioides immitis,
Cryptococcus neoformans, Histoplasma capsulatum, Pseudallescheria
boydii, Sporothrix schenckii and Trichosporon beigelii.  Superficial
infections of the skin caused by dermatophytes are of lesser
significance as public health problems in terms of morbidity and
mortality, but nevertheless merit imaginative new approaches in

Currently, 10 percent of all nosocomial bloodstream infections are
caused by Candida species, with an attributable mortality of 38
percent.  Patients at high risk for these infections include those
neutropenic or likely to become neutropenic because of treatment for
leukemia, solid tumors, or bone marrow transplants, as well as
premature infants and burn patients.  Similarly, Aspergillus species
carry a high attributable mortality and are a significant cause of
nosocomial pneumonia, especially in bone marrow transplant patients.

It has been estimated that 13 million cases of mycotic vulvovaginitis
occur annually in the United States.  Candida species are the most
important fungal agents of this disease.  It was estimated in the
early 1980s, on the basis of skin tests, that there are between
25,000 and 100,000 new infections with Coccidioides immitis each
year.  There is an ongoing epidemic of coccidioidomycosis in highly
endemic areas of the American Southwest where the reported annual
incidence since 1991 has increased more than ten fold over that of
previous years.  Although the majority of cases occur in
immunocompetent individuals, the incidence in HIV seropositive
individuals has been found to be as high as 25 percent.  This figure
is similar to the incidence of histoplasmosis in HIV seropositive
individuals in the areas highly endemic for Histoplasma capsulatum.

Increased incidence also has been documented for infections with
Cryptococcus neoformans.  A study from the Centers for Disease
Control and Prevention found that the incidence of cryptococcal
disease in the U.S. increased nearly five-fold from 1980 to 1989.
The majority of cases occur in immunocompromised patients such as
those with AIDS or those undergoing immunosuppression for renal
allografts, however, a subset of patients has no identified
underlying disease.

Currently the mycology program in the DMID, NIAID consists primarily
of investigator initiated research project grants focusing on the
biology (molecular biology, immunology, biochemistry and cell
biology) of the medically important fungi.  An infrastructure, the
Mycoses Study Group, dedicated to clinical trials of antifungal
agents in invasive mycoses is supported through the contract
mechanism.  An active basic research program in mycology is of
crucial importance to help resolve the serious public health problem
of fungal disease.

Scope of Research

The NIAID recognizes the importance of maintaining its programmatic
emphasis in mycology and fungal disease research.  The goal of this
program is to increase understanding of the biology and host-pathogen
interactions of the medically important fungi.  This fundamental
knowledge will be applied to the development of new and improved
strategies for the prevention, diagnosis, and therapy of the mycoses.

The NIAID wishes to develop multidisciplinary mycology research units
to serve as foci for innovative new research in fungal diseases.
These units will be funded as program project grants.  To achieve
medical and public health relevance, studies should involve the use
of clinical isolates and, where appropriate, clinical materials,
including human cells.  The areas of particular interest to the NIAID
include, but are not restricted to, the following:

o  cellular and molecular biology of the medically relevant fungi
(cell biology, genetics, genome structure, gene expression, gene

o  virulence factors and mechanisms of pathogenesis

o  host-pathogen interactions (including the role of the immune
system in resistance, pathogenesis, and recovery)

o  development of approaches to immunotherapy (antibody or
cytokine-based therapy)

o  development of approaches for fungal vaccines

o  animal model systems for studies of pathogenesis, fungal vaccines,
and antifungal drugs

o  improved methods of identifying, diagnosing and treating fungal

o  studies of fungal physiology, biochemistry and metabolism, leading
to a better understanding of susceptibility and resistance to
antifungal agents

It is anticipated that, in order to achieve these research goals, a
given program project would involve three to five projects and common
resources provided by the cores.  The orientation could be either
organism-specific, with multiple individuals and disciplines focused
on a single fungus of medical importance, or theme specific, with
different medically important fungi serving as models to address
closely related areas of research emphasis.  For example, a program
project focused on development of approaches to fungal vaccines would
have a common goal, would allow for interdisciplinary projects to
draw upon discipline-specific strengths, and requires key components
from the above list of research areas.  Projects may involve
collaboration among investigators at several institutions.
Consortium arrangements should follow the NIH Guide outlined in
"Guidelines for Establishing & Operating Consortium Grants, January,
1989."   These are available from the individuals listed under


Project directors should budget for an annual one day progress review
meeting at a site to be designated (either in Bethesda or in
association with a relevant national meeting).



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are 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 must 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 must 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 must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) 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 is defined as 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 excluded.  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.

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.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not support
applications that do not comply.


Prospective applicants are asked to submit, by February 5, 1994, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator, and the number and title of this RFA.
Prospective applicants are also asked to submit a list of the key
investigators and their institution(s).  Although the letter of
intent is not required, is not binding, does not commit the sender to
submit an application, and does not enter into the review of
subsequent applications, the information that it contains allows
NIAID 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. Olivia Preble at the
address listed under INQUIRIES.


Applications are to be submitted on form PHS 398 (rev. 9/91), the
standard application form for research grants.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone 301/710-0267.  Applicants
must adhere to the format and requirements specified in the PHS 398
application kit.

For purposes of identification and processing, mark "YES" in item 2a
on  the face page of the application and type in the RFA number
AI-94-009 and the title "MYCOLOGY RESEARCH UNITS."  The RFA label
available in the form PHS 398 must be affixed to the bottom of the
face page of the original 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.

The signed, typewritten original of the application, including the
Checklist, and three exact single-sided copies must be sent to:

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

At the time of submission, two additional copies and all five sets of
appendices must also be sent to Dr. Olivia Preble at the address
listed under INQUIRIES.

To ensure their review, applications must be received by both the
Division of Research Grants and Dr. Olivia Preble by March 18, 1994.
Applications not received by this receipt date will be considered
non-responsive and will be returned to the applicant without review.

If the application submitted in response to this RFA is substantially
similar to a grant application already submitted to the NIH for
review, but has not yet been reviewed, the applicant will be asked to
withdraw either the pending application or the new one.  Simultaneous
submission of essentially identical applications will not be allowed,
nor will essentially identical applications be reviewed by different
review committees.  Therefore, an application cannot be submitted in
response to this RFA that is essentially identical to one that has
already been reviewed.  This does not preclude the submission of
substantial revisions of applications already reviewed, but such
applications must include an introduction addressing the previous


Review Procedures

Applications will be reviewed by DRG staff for completeness and by
NIAID staff to determine administrative and programmatic
responsiveness to this RFA.  Those judged to be incomplete or
nonresponsive will be returned to the applicant without review.
Those considered complete and responsive may be subjected to a triage
review by an NIAID peer review group to determine their scientific
merit relative to the other applications submitted in response to
this RFA.  The NIAID will withdraw from competition those
applications judged by the triage peer review group to be
noncompetitive for award and will so notify the applicant
investigator and the institutional business official.  Those
applications judged to be competitive for award will be reviewed for
scientific and technical merit by a Review Committee convened by the
Division of Extramural Activities, NIAID.  The second level of review
will be provided by the National Advisory Allergy and Infectious
Diseases Council.

Review Criteria

The review criteria for P01 grant applications are the review
criteria for large, multicomponent, interdisciplinary program
projects as outlined in the NIAID brochure, Program Project and
Center Grants.  The program project grant application should include
a justification for the appropriateness of that granting mechanism.
The distinguishing features of a program project grant include:

o  A unifying well-defined goal or problem area of research to which
each project relates and contributes, thereby producing a research
environment that allows each research effort to share the creative
strengths of others.

o  A program director who possesses recognized scientific and
administrative competence; he/she must show a substantial commitment
of time and effort to the program and exercise leadership in its
quality control.

o  Each research project must, as assessed by peer review, stand on
its own independent scientific merit, as well as complement other
projects whenever feasible.

o  These multiple projects require the participation of established
investigators in several disciplines, or investigators with special
expertise in several areas of one discipline.  All investigators must
contribute to and share in the responsibilities of fulfilling the
program objective.

o  Ability of the proposed research to provide knowledge of medically
important fungi, which will result in improvement in the prevention,
diagnosis, and treatment of fungal infections.

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 could be included
with the application.


Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program needs and
balance, and the availability of funds.  The totality of the awarded
projects will reflect the diversity of the medically relevant fungi.


Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Requests for the NIAID Information Brochure on Program Project and
Center Grants AND the document (containing updated instructions)
FOR PROGRAM PROJECTS," as well as inquiries regarding programmatic
issues may be directed to:

Dennis M. Dixon, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A34
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7728
FAX:  (301) 402-2508
Email:  dmd@exec.niaid.pc.niaid.nih.gov

Direct inquiries regarding review issues, address the letter of
intent to, and mail two copies of the application and all five sets
of appendices to:

Olivia Preble, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C20
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Todd C. Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B35
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075


Letter of Intent Receipt Date:  February 5, 1994
Application Receipt Date:       March 18, 1994
Scientific Review Date:         July 1994
Advisory Council Date:          September 1994
Earliest Date of Award:         December 1994


This program is described in the Catalog of Federal Domestic
Assistance, No. 93.856 - Microbiology & Infectious Diseases Research.
Awards will be made 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 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.


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