Full Text PA-96-053
 
GENDER IN THE PATHOGENESIS OF AUTOIMMUNITY: MECHANISMS
 
NIH GUIDE, Volume 25, Number 15, May 10, 1996
 
PA NUMBER:  PA-96-053
 
P.T. 34

Keywords: 
  Autoimmunity 
  Pathogenesis 

 
National Institute of Allergy and Infectious Diseases
National Institute of Neurological Disorders and Stroke
National Institute of Diabetes, Digestive and Kidney Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Dental Research
Office of Research on Women's Health
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases gives
special consideration for funding to scientifically meritorious
applications in response to Program Announcements.  Program
Announcements identify areas of ongoing research emphasis for the
NIAID.
 
The National Institute of Allergy and Infectious Diseases (NIAID),
National Institute of Neurological Disorders and Stroke (NINDS),
National Institute of Diabetes, Digestive and Kidney Diseases
(NIDDK), National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS), National Institute of Dental Research (NIDR), and
the Office of Research on Women's Health (ORWH) invite applications
for basic studies that will increase knowledge of the mechanisms by
which gender influences the development of autoimmune disease and the
regulation of the immune response in individuals with these diseases.
Although it is clear that autoimmune diseases disproportionately
affect women, the reasons for this are not clear.  Research into the
basic mechanisms by which sex hormones or non-hormonal gender
differences affect the immune response and protect from or contribute
to a break in self tolerance should allow for the development of
improved therapeutic and preventive strategies for autoimmune
disease.
 
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 Program
Announcement (PA), Mechanism of Gender's Effect in Pathogenesis of
Autoimmunity, is 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 20402-0325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
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.
 
MECHANISM OF SUPPORT
 
Traditional research project grant (R01), FIRST (R29), and small
research grants (R03) may be submitted in response to this
announcement.  The total project period for an application submitted
in response to this PA may not exceed five years; a foreign
application may not request more than three years of support.
 
NIAID uses R03 grants 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 available from the program staff listed under INQUIRIES.
 
NINDS and NIAMS do not utilize the R03 mechanism.
 
RESEARCH OBJECTIVES
 
Background
 
Autoimmune diseases, which disproportionately affect women, are a
significant source of morbidity, often severe, in the population,
costing billions of dollars annually in health care expenses and lost
productivity.  Systemic lupus erythematosus (SLE) affects women seven
to nine times more frequently than men; Sj"gren's syndrome is found
nine times as frequently in women; multiple sclerosis is twice as
common in women;  rheumatoid arthritis is three to four times as
common; and autoimmune thyroid disease, including both thyroiditis
and Grave's disease, is six to ten times as common in women as men.
Many of these diseases increase in frequency after puberty,
suggesting a role for sex hormones in their pathogenesis.  However,
autoimmune disease is also more common in prepubertal females than
prepubertal males.  Furthermore, pregnancy may exacerbate the course
of some autoimmune diseases, while it ameliorates the course of other
autoimmune diseases.  Thus, factors other than sex hormones may be
important in modulating the immune response in these diseases.  Both
human and animal studies suggest that the genetic background plays a
significant role in the development of autoimmune disease.  For
example, although estrogens have been shown to accelerate the
development of autoimmune disease in certain inherited animal models
of SLE, and testosterone has been shown to inhibit the onset of
disease in these same models, other models of SLE show minimal
effects of sex hormones, suggesting an interaction of genetic and
hormonal influences on the immune response.  Additionally, data in
both humans with multiple sclerosis and an animal model of this
disease suggest differences in the response of males and females in
the development of tolerance after feeding of oral antigens, implying
that the efficacy of immunotherapies may be in part gender
associated.
 
A recent NIH-sponsored meeting on GENDER AND AUTOIMMUNITY reviewed
the state of current knowledge concerning the reasons women
disproportionally are afflicted by autoimmune diseases and identified
several areas in which further research is needed.  The role of sex
hormones in modulating the normal and autoreactive immune response is
not clear and more information is needed at the molecular and
cellular level.  Non-hormonal influences of gender, including
imprinting, genetic, and environmental factors may also be important,
but are not clearly defined.  The breakdown of tolerance to self is a
key component of autoimmune diseases, yet the mechanisms by which
gender affects the development, maintenance, or loss of tolerance are
unknown.
 
Objectives and Scope
 
This PA will support basic research on the role of gender in the
pathogenesis of autoimmunity and autoimmune diseases.  Relevant
topics include, but are not limited to:
 
o  the role of non-hormonal intrinsic aspects of gender, including
X-chromosome inactivation and other genetic/chromosomal factors in
regulating the immune response;
 
o  neuroimmunological and neuroendocrine influences on the
development of an autoreactive response;
 
o  genetic influences on the immune response of males versus females;
 
o  examination of the effects of sex hormones on the immune response
at the molecular and cellular level.  Examples include:  sex hormone
effects on T cell subset differentiation, i.e., Th1 versus Th2;
cytokine networks; thymic selection; B cell repertoire development
and activation; antigen presenting cell function and cellular
trafficking;
 
o  mechanism(s) by which the autoreactive immune response is altered
during pregnancy and in the post partum period;
 
o  the role of imprinting in the development of autoimmune disease;
and
 
o  mechanism(s) by which gender regulates the response to therapies
for autoimmune disease.
 
The above examples of research topics and approaches are not meant to
be all inclusive or restrictive.  Investigators are encouraged to
develop their own innovative hypothesis-driven approaches to achieve
the goals of this PA.
 
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 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.
 
APPLICATION PROCEDURES
 
Applicants are strongly encouraged to call program staff early in
project development 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) 435-0714, email:
asknih@odrockm1.od.nih.gov.
 
Each application must be identified by checking "YES" on line 2 of
the PHS face page, and the number and title of this program
announcement must be typed in section 2.
 
The completed original and five 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)
 
R03 APPLICANTS ONLY: Direct inquiries regarding review issues and
special instructions for application preparation and mail two copies
of the R03 application and all five sets of any appendices to:
 
Stanley Oakes, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C06
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-7042
FAX:  (301) 402-2638
Email:  stanley_oaks@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
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 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
 
Applicants for all Small Research (R03) grants must see the REVIEW
CONSIDERATIONS section of the notice "SMALL RESEARCH GRANTS - NIAID,"
which appeared in the NIH Guide for Grants and Contracts, Vol. 22,
No. 9, March 22, 1996, and are available from the NIAID program staff
listed under INQUIRIES.
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit 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 about 50 percent of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council.
 
Review Criteria
 
o  scientific, technical, or medical significance and originality of
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.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment. Concerns expressed by the initial review group
about any of these factors may influence the recommendation of the
National Advisory Allergy and Infectious Diseases Council concerning
funding of that application.
 
AWARD CRITERIA
 
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.
 
INQUIRIES
 
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Elaine Collier, M.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A20
6003 Executive Boulevard - MSC 7640
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  ec5x@nih.gov
 
A. P. Kerza-Kwiatecki, Ph. D.
Division of Demyelinating, Atrophic, and Dementing Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 804
7550 Wisconsin Avenue - MSC 9150
Bethesda, MD  20892-9150
Telephone:  (301) 496-1431
FAX:  (301) 402-2060
Email:  ak45w@nih.gov
 
Ronald Margolis, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN.12J
45 Center Drive - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 480-3503
Email:  rm76f@nih.gov
 
Susana Serrate-Sztein, M.D.
Arthritis Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS37G
Telephone:  (301) 594-5032
FAX:  (301) 480-4543
Email:  ss86e@nih.gov
 
Eleni Kousvelari, D.D.S., D.Sc.
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 18A
Telephone:  (301) 594-2427
FAX:  (301) 480-8318
Email:  ek17w@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Mrs. Pamela Fleming
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B30
6003 Executive Boulevard - MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  pf49e@nih.gov
 
Ms. Dianna Jessee
Division of Extramural Affairs
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
7550 Wisconsin Avenue - MSC 9190
Bethesda, MD  20892-9190
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  dj35j@nih.gov
 
Ms. Kim Law
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 6AS-49A
45 Center Drive - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8869
FAX:  (301) 480-3404
Email:  LAWK@EP.NIDDK.NIH.GOV
 
Ms. Carol Fitzpatrick
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS43K
Telephone:  (301) 594-3506
FAX:  (301) 480-4543
Email:  fitzpatric@ep.niams.nih.gov
 
Mr. Martin Rubinstein
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AS-55
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  mr49c@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 Citation is No. 93.855 -
Immunology, Allergy, and Transplantation Research, No. 93.853 -
Clinical Research of Neurological Disorders and Stroke, No. 93.847 -
Diabetes, Endocrinology, and Metabolic Diseases, No. 93.121 - Oral
Diseases and Disorders Research, and No. 93.846 - Arthritis,
Musculoskeletal and Skin 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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