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Full Text PA-96-067
NIH GUIDE, Volume 25, Number 25, July 26, 1996
PA NUMBER:  PA-96-067
P.T. 34


National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases gives
special consideration for funding to scientifically meritorious
applications in response to Program Announcements.  Program
Announcements (PA) identify areas of ongoing research emphasis for
the NIAID.
The Division of Microbiology and Infectious Diseases (DMID) of the
National Institute of Allergy and Infectious Diseases (NIAID) invites
applications for research on molecular correlates of pathogenesis in
selected parasitic diseases.  The purpose of this PA is to encourage
research to identify pathophysiologic mechanisms underlying those
features most likely to be associated with adverse clinical outcomes
of infection.  This information will contribute to the determination
of appropriate case definitions, development of new disease
intervention strategies, and selection of appropriate endpoints to be
used in clinical trials of candidate vaccines and new therapies.
Diseases of interest are severe malaria, severe hepatosplenic
schistosomiasis, and leishmaniasis (other than self-limited,
cutaneous forms of disease). Studies in human populations at risk in
endemic areas are particularly encouraged.
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 PA,
Molecular Correlates of Pathogenesis in Infectious Diseases, 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 20402-0325 (telephone 202-512-1800).
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) award (R29).
Traditional research project grant (R01) and FIRST (R29) award
applications may be submitted in response to this program
announcement.  Funds and time requested should be appropriate for the
research proposed.
In a wide variety of infections, especially those that are chronic in
nature, disease is a result of complex host-pathogen interactions.
The identification of specific factors, e.g., host genetic markers or
specific host responses, which correlate with clinical expression of
disease may lead to defining selected subgroups of patients at
greater risk of morbidity and mortality as a result of infection.
Such well-characterized factors may serve as sentinel markers of
accelerating disease, as useful indicators that can be monitored for
clinical management and probable outcomes, and as surrogate endpoints
in clinical studies.  Thus, the expected advances from studies
supported under this initiative would be the identification and
validation of molecular markers associated with a particular clinical
outcome, and demonstration of their utility in case detection or case
management in malaria, schistosomiasis, and leishmaniasis.
Studies have identified a number of potential molecular correlates of
pathogenesis in selected animal models of human parasitic diseases.
For example, either deficient induction of Interferon-gamma (IFN-g)
or increased production of TGF-beta, IL-4 or IL-10 is associated with
progressive leishmaniasis in mice.  Correlative studies have
suggested a similar pathogenetic picture occurs in man. Treatment
with recombinant IFN-g has proven beneficial in leishmaniasis
NIAID-supported work has already demonstrated that plasma levels of
the cytokine tumor necrosis factor (TNF) are elevated in adults with
severe malaria and in children with acute Plasmodium falciparum
infections.  Other work has demonstrated that a polymorphism in the
TNF-alpha promoter controls the level of gene expression and
correlates with severe malaria.  TNF-alpha has pleiotropic effects
and may therefore contribute to the multisystem pathology seen in
severe malaria.  Other cytokines, however, have also been shown to be
elevated and may play important roles in pathology in this disease.
Consistent with this latter view are recent observations that
infusion of monoclonal antibodies to TNF-alpha results in a reduction
in fever without a significant effect on other outcomes.  Recent
studies of HLA associations with severe malaria have enabled
investigators to use reverse immunogenetic approaches to construct
novel candidate vaccines.
In these parasitic diseases, however, molecular markers have not been
identified, confirmed or validated in humans. A broad-based
initiative encouraging multidisciplinary studies focussed on the
pathologic outcomes is therefore warranted to define at the molecular
level pathogenetic mechanisms operating on both sides of the
host-parasite interaction.  The results obtained will subsequently be
of benefit in devising new interventions as well as in identifying
surrogate markers of efficacy.  For example, reliable and precise
case definitions of malaria have proven particularly problematic in
recent clinical trials, resulting in substantial controversy over the
interpretation of results.  The availability of relevant surrogate
markers could contribute substantively to accelerated development and
clinical evaluation of novel interventions, enhance the acceptability
and application of such interventions where appropriate, and improve
the effectiveness and reduce the cost of applying such interventions
by permitting targeting of populations at risk.  Furthermore, such
results will provide important applications and insights for other
diseases in which similar pathogenic mechanisms operate.
Research Objectives and Experimental Approaches
The objective of this initiative is to identify and delineate at the
molecular level the pathophysiologic mechanisms underlying adverse
outcomes and their associated clinical features in malaria,
schistosomiasis, and leishmaniasis.  An improved understanding of the
pathophysiology of these clinical manifestations would facilitate
targeted, rational development of new biologic and pharmacologic
intervention.  In addition, for development of vaccines, it will be
beneficial to understand and thus avoid these pathologic mechanisms.
Molecular markers of pathogenesis may also serve as surrogates for
determining the efficacy of candidate vaccines and other prophylactic
or therapeutic interventions.
Studies in human populations are particularly encouraged. For
example, relevant projects would address one or more of the following
o  Identification of molecular genetic markers indicative of an
increased susceptibility to an adverse outcome, e.g., cerebral
malaria, severe malarial anemia, severe schistosomiasis-associated
hepatosplenomegaly, and assessment of their utility in a clinical
o  Identification and/or validation at the molecular level of
cytokine responses that by their nature, magnitude or kinetics,
contribute to pathologic outcomes, and their detection and assessment
of utility in the clinical setting
o  Identification of specific moieties of parasite origin that are
associated with increased pathogenicity, and their detection in the
clinical setting
o  Demonstration of the clinical utility of selected, assayable
molecular markers in the medical management of severe disease or for
assessment of the need for prophylaxis
It is the policy of the NIH that women and members of minority groups
and their sub-populations 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
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 printed in
the NIH Guide for Grants and Contracts, Volume 23, Number 11, March
18, 1994.
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.
Applicants may call NIAID program staff with any questions regarding
the responsiveness of their proposed project to the goals of this PA.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted on the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Office of Extramural
Outreach and Information, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301)
710-0267, email: asknih@odrockm1.od.nih.gov.
FIRST (R29) applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
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 Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the 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.  In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box must
be marked.
The completed original and five legible, single-sided copies of the
application must be sent or delivered to:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by study sections of the Division of Research
Grants, NIH, in accordance with the standard NIH peer review
As part of the initial merit review, all applications will receive a
written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally
the top half of the applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory.
Review Criteria
o  scientific, technical, or medical significance and originality of
the proposed research;
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
o  availability of the resources necessary to perform the research;
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
o  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
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions:  quality of the proposed project as
determined by peer review, program balance among research areas of
the announcement, availability of funds.
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic (eligibility and
responsiveness) issues to:
B. Fenton Hall, M.D., Ph.D.
Division of Microbiology an Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A-09
6003 Executive Boulevard MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-2544
FAX:  (301) 402-0659
Email:  bh24q@nih.gov
Direct inquiries regarding fiscal matters to:
Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B-35
BETHESDA MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  tb22j@nih.gov
This program is described in the Catalog of Federal Domestic
Assistance No. 93.856, Microbiology and Infectious Disease Research.
Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as 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 Health Systems Agency 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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