Full Text PA-97-053
NIH GUIDE, Volume 26, Number 12, April 11, 1997
PA NUMBER:  PA-97-053
P.T. 34

  Digestive Diseases & Disorders 
  Infectious Diseases/Agents 

National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
The National Institute of Allergy and Infectious Diseases (NIAID) and
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invite investigator-initiated applications in research
emphasis areas focused on infection and disease caused by enteric and
hepatic pathogens.  The PA identifies organism-specific gaps and
opportunities with potential to lead to new diagnostics, vaccines,
therapies, or other control strategies.  Of special interest are:
the protective immune response and strategies to invoke it;
mechanisms determining the outcome of infection as well as mechanisms
of pathogenesis and persistence; variability and genomic organization
and component structure/function; modes of transmission, reservoirs
of infection, and molecular epidemiology; and application of new
technologies and scientific advances to vaccine and therapy
development.  Multi-disciplinary research is encouraged.
This PA's research emphasis areas for enteric and hepatic diseases
were, in part, identified by a comprehensive NIAID external program
review conducted in the summer of 1996.  The report can be accessed
via the Internet through the NIAID HOMEPAGE at URL
"http://niaid.nih.gov" or directly at:
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,
Enteric and Hepatic Infectious Diseases, is related to the priority
areas of immunization and infectious diseases and chronic disabling
conditions.  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) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-0325
(telephone 202-512-1800).
Applications may be submitted by 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.  Domestic and foreign
institutions are eligible to apply for R01 and R03 grants.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
Traditional research project grant (R01), FIRST award (R29), and
small research grant (R03) applications may be submitted in response
to this program announcement.  Applications for R01 grants may
request up to five years of support; applications for R29 grants must
request five years of support; and applications for R03 grants may
request up to three years of support (See APPLICATION PROCEDURES
below for instructions on R03 applications).
The NIAID and NIDDK use R03 grants to support highly innovative
feasibility or pilot projects.  R03 applicants are encouraged to
establish collaborations with the NIAID supported Hepatitis C
Cooperative Research Centers or NIDDK supported Digestive Diseases
Centers Program.
Infectious enteric and hepatic pathogens cause many different acute
and chronic diseases which affect several organ systems.
Enteric Infectious Diseases:  Agents infecting the gut cause diarrhea
- the second leading cause of morbidity and mortality worldwide.
They especially affect children less than five years of age.  Vibrio
cholera, diarrheagenic E. coli, Campylobacter, Salmonella, Shigella
and rotavirus continue to cause tremendous numbers of infections and
deaths each year in the developing world as well as significant
morbidity in travelers to endemic areas.  Some are already public
health threats in the United States and some have potential to emerge
and become such threats.
Sometimes infection with these diarrheagenic agents leads to severe
chronic sequelae. Enterohemorraghic Escherichia coli (EHEC) is
associated with secondary severe kidney damage (hemolytic uremic
syndrome) resulting in death or impaired kidney function.
Campylobacter jejuni is the second most common cause of bacterial
diarrhea.  Infection with it is the most often recognized precedent
to Guillain Barre Syndrome (GBS), an acute and chronic neuromuscular
disease. Antibiotic resistance to C. jejuni is rapidly increasing.
[Check "http://www.niaid.nih.gov/dmid/gbssumfi.htm" on the internet
for a summary of a GBS/C.jenuni workshop held at NIH in the summer of
Finally, infection with the enteric pathogen Helicobacter pylori
causes ulcers.
Hepatic Infectious Diseases:  Viruses cause both the acute and
chronic liver disease (hepatitis, cirrhosis) and produce significant
morbidity and mortality.  Because of their chronic manifestations
hepatitis B virus (HBV) and hepatitis C virus (HCV) have the greatest
impact.  Respectively, there are 250,000 and 150,000 annual
infections with HBV and HCV in the United States.  Since HCV is more
apt to become a chronic infection there are 4,000,000 chronic HCV
carriers compared to 1,250,000 chronic HBV carriers in this country.
In the United States, each agent causes about $800 million in annual
direct health care costs; liver transplants resulting from hepatitis
infection add substantial additional costs.  Highly effective
vaccines to prevent hepatitis B are available but underutilized;
better therapies are needed.  Effective means to treat chronic
carriers and vaccines to prevent hepatitis C are urgently needed.
HCV is associated with extra-hepatic disease manifestations.
Research Objectives and Scope
The Enteric Diseases and Viral Hepatitis programs (NIAID) and the
Division of Digestive Diseases and Nutrition (NIDDK) seek to support
basic and clinical research with potential to lead to diagnostics,
vaccines, therapies, or other control strategies that will reduce the
disease burden and health costs associated with enteric and hepatic
infectious disease agents.  Significant gaps in current research
support and opportunities to develop new areas have been identified
with the help of external advisors.  This Program Announcement
solicits applications, including multidisciplinary approaches, from
the research community to address these gaps.  Specific, significant
scientific objectives and opportunities include, but are not limited
ENTERIC PATHOGENS (see the following references)
Hemolytic uremic syndrome (HUS) or central nervous system (CNS)
damage due to Shiga or Shiga-like toxins: [1]
o  mechanism(s) of host cell and organ damage
o  mechanism(s) of toxin transport to the blood stream and strategies
to prevent transport
o  crystal structure of SLT-I and II and their receptor complexes
o  new therapeutic strategies for treatment of patients presenting
with bloody diarrhea
Campylobacter jejuni: [1]&[2]
o  animal models of C. jejuni enteritis
o  lipopolysaccharide (LPS) structure
o  virulence factors
o  role of the organism, its components, and the host immune response
in pathogenesis
o  mechanism(s) of inflammatory diarrhea
o  improved diagnostics, including LPS-based
o  epidemiology of the organisms and disease: reservoirs and
o mechanism(s) of antibiotic resistance
Clostridium difficile [NOTE: additional study of the toxin is not
requested]: [1]
o  virulence factors
o  mechanism(s)of pathogenesis
o  host immune response
Helicobacter pylori: [1]
o  mechanism(s) of colonization and persistence
o  role of host immune response in pathology
o  epidemiology: reservoirs and transmission
o  role of H. pylori induced achlorhydria in increased susceptibility
to other enteric pathogens
Caliciviruses and Astrovirus: [1]
o  genomic organization and partial sequence of new isolates as a
means to more effective detection and complete epidemiological
o  contribution to incidence of viral diarrhea and clinical
Immunity and Vaccine Development for Salmonella, Shigella, and
diarrheagenic E. coli: [1] [NOTE: For these pathogens significant
advances have been made with respect to the identification of
virulence factors, understanding of their regulation, and
verification of their role in pathogenesis.  Molecular and genetic
data have spurred vaccine development but effective vaccines are not
yet available.  High priority will be given to collaborative,
multi-disciplinary studies]
o  understanding of protective immunity particularly at the mucosal
surface in animal models and humans and verification of animal model
findings in humans
o  creation of effective vaccine strategies to maximize protective
immunity using humans or animal models
Gastroenteritis due to Salmonella enteriditis
Nucleic Acid Vaccines for:
o  bacterial enteric pathogens
o  non-toxic mutants of Shiga toxin(s)
o  enteric viruses
Host Resistance to Enteric Pathogens: [1]
o  role of normal commensal flora
o  role of immune tolerance in establishment and maintenance of
normal commensal flora
o  pathogen-flora interaction and impact on host resistance to
o  probiotic alteration of normal flora and role in preventing and
treating disease.
Viral and host factors and the mechanisms by which they operate and
interact to:
o  determine the outcome of viral infection,
o  maintain viral persistence,
o  cause pathogenesis,
o  influence disease progression, and
o  alter liver function, physiology, cell biology, and architecture
[NOTE that for HBV studies in the woodchuck/woodchuck hepatitis virus
model are especially encouraged] [The NIDDK encourages applications
with the overall scientific aim is the elucidation of liver
physiology and/or pathogenesis]
Model Systems
o  development of in vitro, cell culture and organ-like systems,
animal models including novel systems such as mice with human livers.
[Special need for HCV.]  [NOTE that the NIDDK encourages applications
generating new animal models applicable to liver disease-oriented
o  studies related to examples in previous item, infection and its
prevention [Special need for HCV], and replication.
Adaptation of research findings to preventive and therapeutic
strategies including assay development.
Definition of the protective immune response to HCV, i.e., the
response leading to recovery including roles of B cells, T cells, and
the immune cascade.
Vaccine development for HCV.
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
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 the
program staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
Applications are to be submitted on the grant application for 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 Division 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.nih.gov.  The title and number of the program
announcement must be typed in Section 2 on the face page of the
The completed, signed original and five legible, single-sided copies
of applications must be sent or delivered to:
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
NIAID and NIDDK use small grants (R03) submitted in response to this
PA to support small, highly innovative or pilot projects.  Applicants
for R03 grants may request up to $50,000 annual direct costs for a
period not to exceed three years.  Funds and time requested should be
appropriate for the research proposed.  Applicants for R03 grants
must follow the special application guidelines and Terms and
Conditions of Award in the NIAID SMALL RESEARCH GRANTS brochure
(September 1996); this brochure is available via the WWW at:
The NIH Policy Update on Acceptance for Review of Unsolicited
Applications that Request More Than $500,000 Direct Cost for Any One
Year applies to applications in response to this PA.  The Policy
Update was published in the NIH Guide for Grants and Contracts, Vol.
25, No. 14, May 3, 1996, and became effective June 1, 1996.
Potential applicants must contact the appropriate program staff
listed in INQUIRIES to initiate clearance processes for acceptance of
their applications.
Review Procedures
Applications will be assigned on the basis of established PHS
referral guidelines.  Incomplete applications will be returned to the
applicant without further consideration.  R01 and R29 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 procedures. 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 of review by the appropriate national advisory council.
R03 applications that are complete will be evaluated by an
appropriate peer review group convened by the sponsoring institutes.
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.  For applications assigned to the
NIAID and NIDDK, 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 program
announcement, and availability of funds.
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Inquiries regarding programmatic issues may be directed to:
Leslye D. Johnson, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3A22 - MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-7051
FAX:  (301) 402-1456
Email:  lj7m@nih.gov
Dennis R. Lang, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3A21 - MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-7051
FAX:  (301) 402-1456
Email:  dl73v@nih.gov
Frank Hamilton, M.D., M.P.H.
Digestive Diseases Program Branch
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8877
FAX:  (301) 480-8300
Email:  fh14e@nih.gov
Thomas F. Kresina, Ph.D.
Liver Diseases Program
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8871
FAX:  (301) 480-8300
Email:  tk13v@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 4B35
Bethesda, MD  20892-7610
Telephone:  (301) 402-5512
FAX:  (301) 480-3780
Email:  tb22j@nih.gov
This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.856 and No. 93.848.  Awards are made under
authorization of the Public Health Service Act, Sec. 301(c), Public
Law 78-410, as amended.  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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