Full Text PA-97-098
 
AUTOIMMUNITY: GENETICS, MECHANISMS, AND SIGNALING
 
NIH Guide, Volume 26, Number 29, August 29, 1997
 
PA NUMBER:  PA-97-098
 
P.T.


Keywords: 

 
National Institute of Allergy and Infectious Diseases 
National Institute of Diabetes and Digestive and Kidney Diseases 
National Institute of Arthritis, Musculoskeletal and Skin Diseases
National Institute on Aging
Office of Research on Women's Health, NIH
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID),
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), National Institute of Arthritis, Musculoskeletal and Skin
Diseases (NIAMS), National Institute on Aging (NIA), and the Office
of Research on Women's Health, National Institutes of Health (NIH)
invite applications for new and innovative investigator-initiated
basic and preclinical research into the immune responses underlying
autoimmune disease and its regulation for preventive or therapeutic
purposes.  Three specific areas of emphasis are highlighted:  1)
genetic susceptibility for autoimmune disease, including the MHC and
other genetic loci;  2) role and regulation of co-stimulation of T
cells in autoimmunity; and 3) signal transduction in the autoreactive
response.
 
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 PA,
"AUTOIMMUNITY: GENETICS, MECHANISMS, AND SIGNALING" related to the
priority area of Diabetes and Chronic Disabling 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
 
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 grants.  Foreign
institutions are not eligible for FIRST awards (R29).  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.
 
MECHANISMS OF SUPPORT
 
Traditional research project grant (R01) AND FIRST award (R29)
applications may be submitted in response to this announcement.
Applications for R01 grants may request up to five (5) years of
support; applications for R29 grants must request five years of
support.
 
Responsibility for the planning, direction, and execution of the
proposed research for all applicable mechanisms of support will be
solely that of the applicant.
 
RESEARCH OBJECTIVES
 
Background
 
Autoimmune diseases result when the immune response is directed at
the body's own tissues.  Autoreactive immune responses may be
initiated in response to either exogenous (from outside the body,
such as a pathogen) or endogenous (from inside the body) antigens in
the context of a genetic background susceptible to autoimmunity.
Antigen is processed and presented to the T cell, whose response can
be affected by the availability of co-stimulatory ligand-receptor
interaction(s).  The interaction of antigen with the T cell in the
context of co-stimulatory signals results in activation of various
signal transduction pathways (see below).  In addition, the
environment of this interaction, including cytokines present, amount
and character of antigen present and co-stimulatory molecules, can
affect the type of response and its intensity.
 
Autoimmune diseases are more common in families.  More than one gene
is thought to underlie this genetic susceptibility with one of the
important genetic loci being the Major Histocompatibility Complex
locus.  Marked progress in mapping areas of genetic susceptibility
has been made for some diseases, including insulin dependent diabetes
mellitus and systemic lupus erythematosus.  For these two diseases,
several of the susceptibility genes map to overlapping regions of the
chromosome suggesting that the same or similar genes may be involved
in the development of these different diseases.  The fine mapping and
identification of the genes should allow the evaluation of the
functional consequences of their gene products.  Evaluation of the
interaction of multiple genes and the environment in the development
of the autoimmune phenotype can follow.  Further understanding of
this process in the development of autoreactive responses could lead
to novel approaches for the prevention or therapy of autoimmune
diseases.
 
Increasingly, basic research has emphasized the importance of more
than one signal for the activation of T cells.  The antigen-T cell
receptor complex is primary, but equally, the presence or absence of
other signals, called co-stimulation, can direct the interaction to
the development of tolerance rather than activation.  Blockade of the
co-stimulatory signal has prevented the development of disease in
animal models of multiple sclerosis, insulin dependent diabetes
mellitus, and systemic lupus erythematosus.  Recently, investigation
of this path in ongoing autoimmune disease suggests that these
molecules may be important in the perpetuation of the autoreactive
response.  The number of these co-stimulatory signals which have been
identified is growing rapidly, initially including the B-7 family,
and now expanded to include the CD40-CD40L family.  With further
understanding of the mechanisms, these molecules could be exploited
to modulate the initiation or progression of autoimmune disease.
 
Finally, much progress has been made in defining the intracellular
and extracellular signaling pathways that mediate the consequences of
the immune response after interaction of antigen and the immune
system.  These include the secretion of cytokines, production of
cytotoxic T cells, activation of phosphoprotein signaling cascades,
activation or repression of transcription factors, activation of cell
death pathways, including apoptosis, and inflammatory cascades.  The
final common pathways of damage include release of proteases, nitric
oxide and superoxide production, antigen-antibody complexes, and
cytokines.  Further understanding of these pathways in the
development and regulation of the response to autoantigens and in
mediating autoimmune disease may allow development of effective and
innovative therapies for autoimmune disease.
 
NIA has responsibility for supporting basic research and training in
fundamental studies of immunology that relate to aging.
 
Research Objectives and Scope
 
The objective of this PA is to encourage the application of advances
in basic immunology to understanding the pathogenesis and regulation
of the immune response to self antigens, focusing specifically on
genetic susceptibility, including the interaction of genes, role of
co-stimulation of immune cells, mechanism of induction, perpetuation,
and tissue injury in the autoreactive response.  Further
understanding of the pathogenic and regulatory processes of the
autoreactive immune response should lead to new approaches for the
prevention or treatment of autoimmune diseases.  Examples of topics
of research interest include, but are not limited to:
 
o  characterization of loci of genetic susceptibility to autoimmune
disease, including overlapping loci for multiple diseases;
characterization of the genes in these loci and their products,
including the functional role of these genes;
 
o  mechanisms and interactions by which genes influence the
susceptibility to development of autoimmune disease;
 
o  characterization of the role of co-stimulatory molecules in the
response to self antigens;
 
o  identification of regulators (agonists and antagonists) of co-
stimulatory molecules in the autoreactive response;
 
o  the role of apoptosis in the pathogenesis of autoimmunity and
autoimmune disease;
 
o  the role of STAT proteins in the autoreactive immune response;
potential for regulation of this response; and
 
o  characterization of cytokine expression and regulation in response
to self antigens
 
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 the
program staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
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 on 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
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email:
asknih@odrockm1.nih.gov.
 
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
PA title must also be typed in section 2.
 
The completed, signed original and five (5) legible, single-sided
copies of the application must be sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
 
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
review.
 
Applicants from institutions that have a General Clinical Research
Centers (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
material.
 
REVIEW CONSIDERATIONS
 
Review Procedures
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Upon receipt, applications will be reviewed for
completeness by the NIH Division of Research Grants.  Incomplete
applications will be returned to the applicant without further
consideration.  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 review by the
appropriate national advisory council.
 
Review Criteria
 
The five criteria to be used in the evaluation of grant applications
are listed below.  To put those criteria in context, the following
information is contained in instructions to the peer reviewers.
 
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health.  The reviewers will comment on the following aspects of the
application in their written critiques in order to judge the
likelihood that the proposed research will have a substantial impact
on the pursuit of these goals.  Each of these criteria will be
addressed and considered by the reviewers in assigning the overall
score weighting them as appropriate for each application.  Note that
the application does not need to be strong in all categories to be
judged likely to have a major scientific impact and thus deserve a
high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is
essential to move a field forward.
 
1.  Significance.  Does this study address an important problem? If
the aims of the application are achieved, how will scientific
knowledge be advanced?  What will be the effect of these studies on
the concepts or methods that drive this field?
 
2.  Approach.  Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?
 
3.  Innovation.  Does the project employ novel concepts, approaches
or method?  Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
 
4.  Investigator.  Is the investigator appropriately trained and well
suited to carry out this work?  Is the work proposed appropriate to
the experience level of the principal investigator and other
researchers (if any)?
 
5.  Environment.  Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements?
Is there evidence of institutional support?
 
The initial review group will also examine: the appropriateness of
proposed project budget and duration; the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects; the provisions for the
protection of human and animal subjects; and the safety of the
research environment.
 
AWARD CRITERIA
 
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, and availability of
funds.
 
INQUIRIES
 
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Inquiries regarding programmatic (research scope and eligibility)
issues may be directed to:
 
Elaine Collier, M.D.
Division of Allergy, Immunology, and Infectious Diseases National
Institute of Allergy and Infectious Diseases 6003 Executive
Boulevard, Room 4A20
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  ec5x@nih.gov
 
Joan T. Harmon, Ph.D.
Chief, Diabetes Research Section
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8808
FAX:  (301) 480-3503
Email:  JOAN_HARMON@NIH.GOV
 
Susana Serrate-Sztein, M.D.
Arthritis Branch
National Institute of Arthritis, Musculoskeletal and Skin Diseases
Natcher Bldg. Rm 5AS37G
Telephone (301) 594-5032
FAX: (301) 480-4543
Internet:  szteins@ep.niams.nih.gov
 
Anna M. McCormick, Ph.D.
Chief, Biology Branch
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Internet: am38k@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Mrs. Pam Fleming
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases 6003 Executive
Boulevard, Room 4B30
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  pf49e@nih.gov
 
Linda Stecklein
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6As-49J
Bethesda, MD  20892-6600
Telephone:  (301) 594-8847
FAX:  (301)480-3504
Email:  steckleinl@ep.niddk.nih.gov
 
Ms. Carol Fitzpatrick
Grants Management Branch
NIAMS, NIH
Natcher Bldg. Rm 5AS43K
Telephone: (301) 594-3506
FAX:  (301) 480-4543
Internet: fitzpatric@ep.niams.nih.gov
 
Mr. Joseph Ellis
Grants Management Officer
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Internet:  je14j@nih.gov
 
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 Citations are No. 93.855 -
Immunology, Allergy, and Transplantation Research, No. 93.847 -
Diabetes, Endocrinology, and Metabolic Diseases, No. 93.846 -
Arthritis, Musculoskeletal and Skin Diseases, and No. 93.366 - Aging
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 encourage all grant 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 EPA and PHS missions to
protect and advance the physical and mental health of the American
people.
 
.

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