MYCOLOGY RESEARCH UNITS

Release Date:  February 2, 1998

RFA:  AI-98-002

P.T.

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date: March 9, 1998
Application Receipt Date:  June 16, 1998

APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA)
MUST BE PREPARED USING A MULTI-PROJECT GRANT APPLICATION FORMAT;
SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN AN
NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-
PROJECT AWARDS."

PURPOSE

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.  Therefore, research must be focused on the
identification and validation of targets for the development of
diagnostics, vaccines or therapeutics for systemic mycotic
infections.

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, Mycology Research Units, 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 Summary Report:  Stock No. 017-001-
00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-
1800).

ELIGIBILITY REQUIREMENTS

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. 
Foreign organizations are not eligible to apply.  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

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

Responsibility for the planning, direction, and execution of the
proposed projects will be solely that of the applicant.  The total
project period may not exceed five years.  At this time, the NIAID
is administratively limiting the duration of P01 grants to four
years; this administrative limitation may change in the future. 
The earliest anticipated award date is January 2, 1999.

FUNDS AVAILABLE

The estimated total funds (direct and indirect) available for the
first year of support for this RFA will be $2.5 million.  In fiscal
year 1999, the NIAID plans to make approximately three awards
related to this RFA.  This level of support is dependent on the
receipt of a sufficient number of applications of high scientific
merit.  Applications may not request budgets in excess of $830,000
in total (direct and indirect) costs in the first year.  The usual
PHS policies governing grants administration and management will
apply.  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, the NIAID has not determined whether or
how this solicitation will be continued beyond the present RFA.

RESEARCH OBJECTIVES

Background

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.

Currently, 10% of all nosocomial bloodstream infections are caused
by Candida species, with an attributable mortality of 38%. 
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.  Systemic
candidiasis is also increasing in non-neutropenic patients
including premature infants, burn patients, surgical and trauma
patients.  Similarly, Aspergillus species carry a high attributable
mortality and are a significant cause of nosocomial pneumonia,
especially in bone marrow transplant patients.

It was estimated in the early 1980's, on the basis of skin tests,
that there are between 25,000 and 100,000 new infections with
Coccidioides immitis each year.  An epidemic of coccidioidomycosis
occurred in highly endemic areas of the American Southwest
beginning in 1991.  Direct medical costs between 1991 and 1993 were
estimated at approximately $45 million in Kern County, California
alone.  In Arizona from 1990 to 1995 the incidence of
coccidioidomycosis increased 144%, with a disproportionate number
of cases occurring in persons >65 years of age and persons infected
with HIV. Estimates of direct medical costs in 1993 based on the
Arizona Hospital Discharge Database were approximately $19 million,
with an estimated average cost per hospitalization of $23,889.

Increased incidence also has been documented for infections with
Cryptococcus neoformans. 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.  A study
from the Centers for Disease Control and Prevention found that the
incidence of cryptococcal disease in the U.S. increased nearly 5
fold from 1980 to 1989. The annual prevalence of cryptococcosis
among HIV infected patients in New York City in 1991 was estimated
to be 6.1 - 8.5%.

Currently the mycology program in the Division of Microbiology and
Infectious Diseases, NIAID, where projects resulting from this RFA
will be based, 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. The
Division of AIDS, NIAID, also supports pre-clinical and clinical
research on AIDS-associated pathogenic fungi (Pneumocystis carinii,
Candida albicans, Cryptococcus neoformans) with an emphasis on drug
development.

The NIAID workshop series in medical mycology has identified
opportunities for basic and clinically relevant research. 
Investigator initiated research project grants are ideally suited
to address most of the research needs.  Progress in medical
mycology has been made through individual and collaborative efforts
in the areas of cellular and molecular biology, genetic systems,
host-pathogen interactions, and application of new technology and
knowledge to address virulence, mechanisms of pathogenesis, and
mechanisms of immune protection.  Comments from the 20-23 August
1997 NIAID Mycology Workshop, Immunology in Medical Mycology: Host
Responses to Fungi, indicated a need for more rapid translation of
basic research observations into clinical application and a need
for the field of mycology to capitalize on preliminary success by
building on initial observations.  The program project mechanism
provides an excellent opportunity to extend beyond the capabilities
of single project grants with collaborations to link multiple
projects with a yield of synergy.

Research Objectives and Scope

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 8-11 June 1994 NIAID Mycology Workshop on Molecular and
Immunologic Approaches to the Diagnosis and Treatment of Systemic
Mycoses identified the particular need for better diagnostic tests
for invasive candidiasis and aspergillosis.  Similarly, these
diseases were identified as priorities for drug development.  These
two diseases are exemplary of some common issues surrounding the
opportunistic systemic mycoses. Limitations in treatment are
confounded by limitations in diagnosis.  Blood cultures are usually
negative in disseminated aspergillosis and often negative in
systemic candidiasis.  Clinical trials evaluating new
antimicrobials or new regimens of existing antimicrobials in high
risk groups often must be constructed around empiric treatment
before a microbiologic diagnosis is proven, and measurement of
successful outcome can involve interpretation of a complex
including signs and symptoms of disease, and indirect evidence of
infection. Accordingly, the workshop recommended development of new
and improved methods for diagnosing fungal infections including but
not limited to methods adapting immunological, nucleic acid,
physiological, or metabolic methods or markers.

The 7-9 September 1995 NIAID Mycology Workshop on Antigenic
Peptides, Glycobiology and Vaccines assessed opportunities in
fungal vaccine research.  Key advances were described in vaccine-
related research with the systemic mycoses and even for the more
conceptually difficult, opportunistic mycoses such as
cryptococcosis and candidiasis (Dixon et al., 1996. Researchers use
molecular immunology and technology to combat fungal pathogens. ASM
News, 62(2)81-84).  The interdisciplinary nature of developing a
preventive or therapeutic vaccine is well suited to the program
project mechanism.

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. For projects to be
deemed responsive, a biological process or entity must be
identified as a potential target for prevention, diagnosis, or
treatment.  Processes or entities that could serve as potential
targets include but are not limited to: cellular and molecular
biology (cell biology, genetics, genome structure, gene expression,
gene manipulation; genomics); virulence factors and mechanisms of
pathogenesis; host-pathogen interactions (including the role of the
immune system in resistance, pathogenesis, and recovery); and
fungal physiology, biochemistry and metabolism.

Research drawing on the preceding disciplines may form the
foundation of the application, but a central focus must be on the
identification and validation of targets for the development of
diagnostics, vaccines or therapeutics for systemic mycotic
infections.  The utility must evaluated in an appropriate in vitro
or in vivo model that demonstrates clinical relevance.

o  Diagnostics.  Examples of targets and validation steps could
include identification of a fungal antigen for a systemic fungal
pathogen or related group of pathogens.  Specific research aims
should include steps for qualitative and quantitative analysis of
the target antigen in an in vitro system. Clinical relevance should
be demonstrated by an appropriate preclinical model or by
application to patient samples.  Ideally, the target would serve
not only to identify a specific infection, but also to track the
course of infection in response to treatment.  Multiple courses of
basic research could be integrated and applied to culminate in a
specific aim that validates the entity or target as a legitimate
diagnostic candidate.

o  Vaccines. The goal is to identify antigens that are
immunoprotective or immunotherapeutic for the systemic mycoses. 
Multiple approaches are encouraged, but the one(s) selected for
study must contain a validation step whereby acquisition of
infection or modification of the course of disease in an
appropriate preclinical model is assessed.  Parallel courses of
study to address methods or models of evaluating vaccine efficacy
for the systemic mycoses are also acceptable.

o  Therapeutics.  Project directors for projects focusing on
therapeutics are encouraged to address or document how the research
approaches are unique or underexploited and are not duplicative of
approaches under extensive industrial development. The areas of
particular interest to the NIAID include, but are not restricted
to: immune based therapy, including antibody; novel approaches to
enhancing antifungal efficacy; and novel approaches to enhancing
antifungal delivery. Novel antimicrobial compounds may be a
component of study if emphasis is to validate new classes or
approaches, but downstream (post validation) drug development and
drug screening are not areas of interest for the purposes of this
RFA.

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, requires key components from the above research areas,
and has the potential to demonstrate true synergy where the project
sum is greater than the addition of individual project components. 
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 INQUIRIES, below.

SPECIAL REQUIREMENTS

Budget for an annual one day progress review meeting of the Project
Directors at a site to be designated (either in Bethesda or in
association with a relevant national meeting).

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 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 103-43).

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 Dr.
Dennis M. Dixon (listed in INQUIRIES below) who may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 9, 1998, 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. 
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. Madelon Halula at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants for P01 grants must follow special application
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR
APPLICATIONS FOR MULTI-PROJECT AWARDS (September 1997); this
brochure is available from NIAID staff listed under INQUIRIES, and
via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 5/95).  Application kits are
available at most institutional offices of sponsored research and
may be obtained from the Division of Extramural Outreach and
Information, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email:
asknih@od.nih.gov.

For purposes of identification and processing, item 2a on the face
page of the application must be marked "YES" and the RFA number
þAI-98-002þ and the words "Mycology Research Units (MRUs)" must be
typed in.

Applications must be received by June 16, 1998.  Applications that
are not received as a single package on the receipt date or that do
not conform to the instructions contained in PHS 398 (rev. 5/95)
Application Kit (as modified in, and superseded by, the NIAID
BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT
AWARDS"), will be judged non-responsive and will be returned to the
applicant.  The RFA label available in the application form PHS 398
must be affixed to the bottom of the face page.  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.

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.

It is highly recommended that the appropriate NIAID program contact
be consulted before submitting the letter of intent and during the
early stages of preparation of the application.  (See program
contact under INQUIRIES).

Submit a signed, typewritten original of the application, including
the checklist, and three signed, exact, single-sided photocopies,
in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional exact copies of the grant
application and all five sets of any appendix material must be sent
to Dr. Madelon Halula at the address listed under INQUIRIES.

Concurrent submission of an R01 and a Component Project of a Multi-
project Application:  Current NIH policy permits a component
research project of a multi-project grant application to be
concurrently submitted as a traditional individual research project
(R01) application.  If, following review, both the multi-project
application and the R01 application are found to be in the fundable
range, the investigator must relinquish the R01 and will not have
the option to withdraw from the multi-project grant.  This is an
NIH policy intended to preserve the scientific integrity of a
multi-project grant, which may be seriously compromised if a strong
component project(s) is removed from the program.  Investigators
wishing to participate in a multi-project grant must be aware of
this policy before making a commitment to the Principal
Investigator and awarding institution.

SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO
THIS RFA

Applicants for P01 grants must follow special application
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR
APPLICATIONS FOR MULTI-PROJECT AWARDS (September 1997); this
brochure is available via the WWW at:
http://www.niaid.nih.gov/ncn/grants/multibron.htm.

The brochure presents specific instructions for sections of the PHS
398 (rev. 5/95) application form that should be completed
differently than usual.  For all other items in the application,
follow the usual instructions on pages 5-20 of the PHS 398 booklet.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the
NIH Center for Scientific Review and for responsiveness by NIAID
staff.  Incomplete and/or non-responsive applications will be
returned to the applicant without further consideration.

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 NIAID 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.  The second level of review will be
provided by the National Advisory Allergy and Infectious Diseases
Council.

Review Criteria

The general criteria for P01 grant applications are presented in
the NIAID brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS (September 1997).

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program balance, and
the availability of funds.

INQUIRIES

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 brochure "INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS" as well as inquiries regarding programmatic
(eligibility and research scope) issues, may be directed to:

Dennis M. Dixon, Ph.D.
Division of Bacteriology and Mycology Branch
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3A06 - MSC 7630
Bethesda, MD  20892- 7630
Telephone:  (301) 496-7728
FAX:  (301) 402-2508
Email:  dd24a@nih.gov

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

Dr. Madelon Halula
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C-16
Bethesda, MD  20892-7610
Telephone:  (301) 496-2550
FAX:  (301) 402-2638
Email:  mh30x@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B-35
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
Email:  tb22j@nih.gov

Schedule

Letter of Intent Receipt Date:  March 9, 1998
Application Receipt Date:       June 16, 1998
Scientific Review Date:         October 1998
Advisory Council Date:          December 1998
Earliest Date of Award:         January 2, 1999

AUTHORITY AND REGULATIONS

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 Citation is Sec. 93.856,
Microbiology and Infectious Diseases Research.  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 PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all
tobacco products.  In addition, Public Law 103-227, the Pro-
Children Act of 1994, prohibits smoking in certain facilities (or
in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early
childhood development services are provided to children.  This is
consistent with the PHS mission to protect and advance the physical
and mental health of the American people.


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