Full Text PA-97-003
 
IMMUNOBIOLOGICAL CONSEQUENCES OF AGING
 
NIH GUIDE, Volume 25, Number 35, October 18, 1996
 
PA NUMBER:  PA-97-003
 
P.T. 34

Keywords: 
  Aging/Gerontology 
  Immunology 
  Biological Sciences 

 
National Institute of Allergy and Infectious Diseases
National Institute on Aging
National Institute of Dental Research
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID),
the National Institute on Aging (NIA), and the National Institute of
Dental Research (NIDR) invite applications for basic immunological
research that will clarify the effects of senescence on immune
function.  NIAID is responsible for promoting research on the basic
structure and functions of the immune system and the changes that
occur in the immune system that initiate or contribute to disease.
NIA has the responsibility for supporting basic research and training
in fundamental studies of immunology that relate to aging.  NIDR is
responsible for age-related changes in the immune system that promote
oral diseases. The three Institutes share the goal of achieving a
better understanding of the immune system during aging.  It has been
well established that overall immune function declines with advancing
age.  However, because the immune system is highly complex, it is
essential to understand the multifaceted nature of the age-related
loss of immune function and to identify the primary changes in immune
mechanisms that lead to the decline in immune competence. It is
assumed that retardation, or reversal, of senescent changes in the
immune system would benefit aging individuals, but the validity of
that assumption, and approaches to perpetuating immunological vigor,
are unclear. Although some important changes that occur as the immune
system ages have been identified, much more work will be required to
address adequately the gaps in knowledge and promising scientific
opportunities.  Therefore, the purpose of this Program Announcement
is to stimulate research that will provide fundamental, conceptual
insight into the rational design of prophylactic and therapeutic
measures for improving the immunobiological health of aging humans.
The status of existing knowledge and fruitful directions for research
in the immunobiology of aging are summarized in the Report of the
Task Force on Immunology and Aging, co-sponsored by NIA and NIAID.
Copies of the report can be obtained by contacting the Program
Officers listed below.
 
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), Immunobiological Consequences of Aging, is
related to the priority areas of diabetes and chronic disabling
conditions and 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).
 
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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards or program project (P01)
grants.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
 
MECHANISM OF SUPPORT
 
Traditional research project grant (R01), FIRST (R29) award, program
project (P01) and small research grant (R03) applications may be
submitted in response to this program announcement.  The total
requested 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, NIA and NIDR use R03 grants to support small highly innovative
or pilot projects. Applicants for NIAID R03 grants may request up to
$50,000 annual direct costs for a period not to exceed one (NIA), two
(NIDR) or three (NIAID) years.  Funds and time requested should be
appropriate for the research proposed.  Applicants for R03 grants
must follow special application guidelines, which are referenced
below and available from the program staff listed under INQUIRIES.
Responsibility for the planning, direction and execution of the
proposed project will be solely that of the applicant.
 
RESEARCH OBJECTIVES
 
Background
 
Owing to its complexity, progress in understanding senescence of the
immune system has been slow and difficult. Reasons for utilizing the
immune system for studies of biological aging include: (a) the broad
knowledge base and a steadily-increasing body of new information
about the cellular and molecular events in immune responses; (b) the
opportunities to perform parallel studies in vitro and in vivo, thus
allowing simultaneous analyses of mechanisms and verification of the
physiological relevance of findings; and (c) the clear, reproducible
effects of senescence on the immune system that have been
demonstrated.  Age-associated changes are evident in both B and T
lymphocytes and, at higher organizational levels, in the thymus,
marrow and lymphoid follicles (evident especially by failure of
germinal center formation).  However, there is a dearth of knowledge
about causal events and mechanisms.  The absence of that essential
knowledge prevents the development of approaches and procedures for
maintaining or improving the immune competence of an aging human
population.  This PA is intended to address that gap in existing
knowledge.
 
Research Objectives and Scope
 
The goal of this PA is to promote the acquisition of new knowledge
about the fundamental effects of senescence on the structure and
functions of the immune system.  HIV infection and sequelae are not
within the scope of this PA.  It is the intent of this PA to promote
basic and preclinical research; therefore, proposals that are
clinically oriented are not within its scope.  Examples of relevant
research topics are listed below; however, the list should not be
construed as complete or restrictive.
 
o  Basic and preclinical research leading to new approaches to
protective and therapeutic immunizations (vaccination) of the elderly
that (a) reflect recent advances in basic knowledge of the immune
system and immunosenescence (e.g., defective B and T cell
costimulation, defective de novo immunological memory, shifts in
populations of naive and memory T cells), and (b) involve the
utilization of selected vectors, DNA vaccines and cytokine-epitope
constructs
 
o  Age-associated changes in the origins, lineages, phenotypic and
functional features of B and T lymphocytes, with emphasis on studies
that define changes in the commitment of hematopoietic progenitor
cells to the lymphocyte and B and T cell pathways of differentiation
 
o  Physiological and intrinsic lifetime, circulation, re-circulation,
homing patterns and proliferative potential of T cells and subsets of
T cells of the elderly, including analyses of receptor and adhesion
molecules, their biosynthesis, cell-surface topography and functions
 
o  Cellular and molecular mechanisms that account for the failure of
de novo germinal center formation in lymphoid follicles of elderly
subjects, the possible senescence of follicular dendritic cells and
associated aberrations in antigen presentation, and the reasons for
the compromised antibody isotype switching and affinity maturation in
the elderly
 
o  Approaches to retarding, preventing or reversing thymic atrophy as
well as systemic studies of the consequences of maintaining vigorous
thymic function throughout life
 
o  Age-related changes in the morphological integrity of mucosal
(regional) lymphoid tissues and in the functional competence of the
cells that participate in immune responses at mucosal sites
 
o  Effects of senescence on B cell receptor and T cell receptor
signaling cascades with attention to receptor phosphorylation,
protein kinases and costimulatory pathways such as the CD28/B7 and
CD40/CD40L pathways
 
o  The role of apoptosis (programmed cell death) in the senescence of
the immune system at cellular and molecular levels with emphasis on
elucidating the molecular pathways that regulate apoptosis
 
o  Molecular mechanisms involved in alterations of aging
monocyte/macrophage functions including phagocytosis, antigen
presentation or production of proinflammatory cytokines, nitric
oxide, reactive oxygen species and prostaglandins.
 
o Age-related effects of aging on autoimmune and allergic responses
 
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
 
R03 APPLICANTS.  Applicants for NIAID R03 grants must follow special
application guidelines, SMALL RESEARCH GRANTS - NIAID, which appeared
in the NIH Guide for Grants and Contracts, Vol. 25, No. 9, March 22,
1996. Applicants for NIA R03 grants must follow the special
application guidelines, PILOT PROJECT RESEARCH GRANT PROGRAM FOR THE
NIA, which appeared in the NIH Guide for Grants and Contracts , Vol.
25, No. 3, February 1996. Applicants for NIDR R03 grants must follow
the guidelines for the SMALL GRANTS PROGRAM, which appeared in the
NIH Guide for Grants and Contracts, Vol. 20, No. 12, March 22, 1991.
NIDR R03 applicants are also required to follow the R03 page
limitations described in the NIH Guide Vol. 22, No. 1, January 8,
1993. Copies of all these guidelines are available from the program
staff listed under INQUIRIES.
 
P01 APPLICANTS AND APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL
DIRECT COSTS.  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 Program
Announcement.  The Policy update was published in the NIH Guide,
Volume 25, Number 14, May 3, 1996, and is effective June 1, 1996.
Both NIAID, NIA and NIDR have (1) policies that require pre-approval
by the Institute before acceptance of Program Project applications
and applications that request $500,000 or more in annual direct costs
and (2) guidelines for preparation of multi-project (including P01)
research grant application.  Potential applicants must contact the
appropriate program staff listed in INQUIRIES below to initiate
clearance processes for acceptance of their applications and to
obtain guidelines for the preparation of P01 applications.
 
Applicants are strongly encouraged to contact 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 face page, and the number and title of this program announcement
must be typed in section 2.
 
R01, R29, AND P01 APPLICANTS ONLY:  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:  The completed original and three legible
single-sided copies of the application must be sent or delivered to
the Division of Research Grants at the above address.
 
For R03 applications submitted to NIAID, 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 Oaks, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C06
Bethesda, MD  20892
Telephone:  (301) 496-7042
FAX:  (301) 402-2638
Email:  so14s@nih.gov
 
For R03 applications submitted to the NIA, submit two additional
exact photocopies of the application directly to:
 
Chief, Scientific Review Office
National Institute on Aging
Gateway Building, Suite 2C212, MSC 9205
7201 Wisconsin Avenue
Bethesda, MD  20892-9205
 
Direct inquiries regarding the NIA R03 program guidelines and
targeted research areas to:
 
Anna M. McCormick, Ph.D.
Biology of Aging Program
National Institute on Aging
Telephone: (301) 496-6402
FAX:  (301) 402-0010
Email: BAPquery@gw.nia.nih.gov
 
For R03 applications submitted to the NIDR, submit two additional
exact photocopies of the application directly to:
 
Willian Gartland, Ph.D.
Division of Extramural Research
National Institute of Dental Research
Building 45, Room 4AN-32
Bethesda, MD  20892-6402
Telephone:  (301) 594-2372
FAX:  (301) 480-8303
Email:  GartlandW@de45.nidr.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
 
R03 APPLICANTS.  Applicants for NIAID R03 grants should read the
special review considerations section in SMALL RESEARCH GRANTS -
NIAID, which appeared in the NIH Guide for Grants and Contracts, Vol.
25, No. 9, March 22, 1996, and are available from the NIAID program
staff listed under INQUIRIES. Applicants for NIA R03 grants should
refer to the review considerations section in PILOT PROJECT RESEARCH
GRANT PROGRAM FOR THE NIA which appeared in the NIH Guide for Grants
and Contracts, Vol. 25, No. 3, February 9, 1996.
 
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. All NIDR R03
applications will be assigned a priority score.
 
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, the
National Advisory Council on Aging or the National Advisory Council
for Dental Research.
 
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, electronic, and telephone inquiries concerning this PA are
encouraged.  The opportunity to clarify any issues or questions from
potential applicants is welcome.
 
Direct requests for the PA and inquiries regarding programmatic
(eligibility and responsiveness; clearance of Program Project and
annual direct costs of $500,000 or more applications; guidelines for
P01 applications) issues to:
 
Helen Quill, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A22
Bethesda, MD  20892-7640
Rockville, MD  20852 (for express mail)
Telephone:  (301) 496-7551
FAX:  (301) 402-2571
Email:  hq1t@nih.gov
 
Dr. Anna M. McCormick
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892
Bethesda, MD  20814 (for express mail)
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  am38k@nih.gov
 
Dennis F. Mangan, Ph.D.
Division of Extramural Research
National Institute of Dental Research
Building, 45, Room 4AN-32F
Bethesda, MD  20892-6402
Telephone:  (301) 594-2421
FAX:  (301) 480-8318
Email:  Dennis.Mangan@nih.gov
 
Direct inquiries regarding fiscal and administrative matters to:
 
Laura Eisenman
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B23
Bethesda, MD  20892-7610**
Rockville, MD  20852 (for express mail)
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  le55d@nih.gov
 
Mr. Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892
Bethesda, MD 20814 (for express mail)
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  je14j@nih.gov
 
Mr. Martin Rubinstein
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN-44A
Bethesda, MD  20892-64-2
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  Martin.Rubinstein@nih.gov
 
AUTHORITY AND REGULATIONS
 
The program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research, No. 93.366 - Aging Research and No. 93.121 - Oral Diseases
and Disorders ResearchAwards 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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