Full Text AI-93-11

THE CAUSES AND CONSEQUENCES OF THYMUS INVOLUTION

NIH GUIDE, Volume 22, Number 6, February 12, 1993

RFA:  AI-93-11

P.T. 34

Keywords: 
  Immune System 
  Physiology, Human 
  Pathophysiology 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  April 1, 1993
Application Receipt Date:  July 21, 1993

PURPOSE

The Division of Allergy, Immunology and Transplantation (DAIT) of the
National Institute of Allergy and Infectious Diseases (NIAID) invites
applications for studies focused on the causes and consequences of
thymus involution.  The purpose of research dealing with thymus
involution is to achieve an understanding of this still largely
mysterious phenomenon.  It is essential to determine whether normal
thymus involution is a vital physiological process that contributes
to sustained vigor of the immune system or, by contrast, leads to
subtle pathological activities of the immune system.  Given that
there are approaches to preventing, retarding or reversing thymus
involution, it is important to determine whether or not interfering
with the process of involution has desirable and beneficial effects
on the immune system.

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 Request
for Applications (RFA), The Causes and Consequences of Thymus
Involution, is related to the priority area of diabetes and chronic
disabling conditions.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-782-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by public and private, foreign and
domestic, for-profit and non-profit organizations, such as
universities, colleges, hospitals, laboratories, units of State and
local governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible to apply for First Independent
Research Support and Transition (FIRST) (R29) awards.  Women and
minority investigators are encouraged to apply.

MECHANISM OF SUPPORT

The mechanisms of support for this program will be the research
project grant (R01) and the FIRST award (R29).  The regulations and
policies that govern the research grant programs of the National
Institutes of Health will prevail.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant.  The total project period may not exceed five
years.  The budget request for an R29 application is restricted to
the amount allowed by NIH for R29s.  The budget request for an R01
application should not exceed $200,000 total direct costs in the
first year.  Neither type of application should request more than 4
percent annual inflationary increases in future years.

This RFA is a one-time solicitation.  Future competing continuation
applications will be considered unsolicited and compete with all
investigator-initiated applications and will be reviewed according to
the customary NIH peer review procedures.

FUNDS AVAILABLE

The estimated total funds (direct and indirect) available for the
first year of support for this RFA will be $800,000.  In fiscal year
1994, the NIAID plans to award at least three projects (R01s or R29s)
submitted in response to this RFA.  This level of support is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  Although this program is provided for in the
financial plans of the NIAID, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.  Funding
beyond the first and subsequent years of the grant will be contingent
upon satisfactory progress during the preceding years, and
availability of funds.

RESEARCH OBJECTIVES

Background

In both humans and laboratory animals, the thymus begins to decrease
in size and cellularity at a time that coincides roughly with sexual
maturity.  The decrease in size/weight is accompanied by altered
histoarchitecture, especially reduction in the volume of the medulla
and thinning of the cortical region.  Histologically, it appears that
the thymus nearly stops generating and exporting T cells.

Thymus involution is not accompanied by a reduction in the number of
peripheral T cells, either in humans or mice.  Either the atrophied
thymus can continue to generate sufficient numbers of T cells or
there are extra-thymic sites of T cell generation.  Evidence for the
latter is accumulating.  For example, the adult athymic ("nude")
mouse displays a significant number of T cells (up to half the number
in euthymic controls).

As animals and humans progress from adolescence to adulthood and
middle life, generation of T cells from extra-thymic sites may become
substantial, possibly reflecting the waning export of T cells by the
thymus.  Recent publications strongly suggest that the liver may
serve as a site of T cell generation, especially during stress.  T
cells originating from extrathymic sites may display a propensity for
recognizing self-antigens.

During the lifetime of mice and humans, there occurs a significant
change in relative proportions of subsets of CD4+ T cells.  There is
a significant increase in the relative (and absolute) number of CD44+
(Pgp-1+) memory or activated T cells and a decrease in the numbers of
naive T cells.  This is accompanied by a change in the potential for
elaboration of different cytokines; in particular, there is an
increase in potential for generating IFN~ and a decrease in
production of IL-2.

The normal physiological causes of thymus involution remain obscure.
Similarly, obscurity surrounds the mechanism for maintaining an
essentially constant number of peripheral T cells throughout life.
How is the number of T cells counted and adjusted in the face of
apparent declining thymus export of T cells?  Equally obscure are the
reasons for the transient thymus involution (with constant peripheral
T cell number) that occurs during pregnancy.  Furthermore, there is
no satisfactory explanation for the exquisite susceptibility to
xenobiotics such as dioxins and nickel ions, nor is it known why
exposure to ionizing radiation apparently rejuvenates the atrophic
thymus.  These and many other questions deserve systematic
investigation.

Research Objectives and Scope

Projects that clearly will enhance understanding of the causes and
physiological/pathological significance of thymus atrophy and will
promote reasonable approaches to preventing or treating immunological
diseases are encouraged.  Research areas of interest include, but are
not limited to:

o  Studies aimed at determining the causes of thymus involution; its
impact on the rate and magnitude of change in the export of T
lymphocytes; and the chronological age and physiological stage at
which T cell generation/export reaches a nadir;

o  Evaluations of the immunological consequences of the decline and
minimization of T cell generation/export by the thymus (e.g., changes
in the T cell repertoire; changes in immunological potential; changes
in the potential for self-reactivity and pathological autoimmunity;
similarities and differences between natural thymus involution and
adult thymectomy);

o  Explorations of extrathymic sites for locations of T cell
generative potential, and characterization of the T cells generated
at those sites;

o  Identification and analysis of long-lasting subsets of T cell
precursors that may be located and/or generated in peripheral
lymphoid or other tissues;

o  Development of procedures to delay thymus involution or to
rejuvenate the involuted thymus, and evaluation of the immunological
consequences of prolonged or restored thymus function; and

o  Analyses of factors that control the mass of the thymus and that
influence the survival and duration of function of thymus grafts
implanted into thymectomized recipients, genetically-athymic
recipients and recipients in which the thymus has involuted.

The scope of this RFA does not include studies on aging of the immune
system. If such applications are received, the Division of Research
Grants (DRG) will assign them to the National Institute on Aging as
unsolicited applications.

Budget requests should include, in the third year, travel funds for
the Principal Investigator to attend a two-day meeting in the
Washington, DC area to review progress and remaining knowledge gaps
and discuss future scientific opportunities with all Principal
Investigators supported under this RFA, as well as other scientists
conducting research related to the objectives and scope of this RFA.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy requires that applicants for NIH clinical research grants
and cooperative agreements include minorities and women in study
populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale MUST be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information must be included in the form PHS 398 in items 1-4 of the
Research Plan AND summarized in item 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of U.S.
racial/ethnic minority populations [i.e., Native Americans (including
American Indians or Alaskan Natives), Asian/Pacific Islanders,
Blacks, and Hispanics].  The rationale for studies on single minority
population groups should be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions including, but not limited to,
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
clinical samples which may be coded for use by the applicant but
could be identified by another source are not excluded.  Every effort
should be made and documented to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the U.S. populations, including minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

Peer review groups need adequate information about the composition of
proposed study populations in all applications involving human
subjects.  To avoid delays in review of such applications, the NIAID
advises that, as a minimum, the application should contain
demographic data about the clinic and/or in-patient population from
which study subjects will be drawn:  average hospital admissions per
year; percentage distribution of Black/Hispanic/other
minority/non-minority populations; gender; etc.  Studies using
non-hospital populations, such as community-based studies, should
provide similar data about populations in the area or region from
which the study subjects will be drawn.  In the absence of current
data, historical demographic information and/or previous recruitment
data for similar studies from the proposed study sites should be
provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 1, 1993, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator, and the number and title of this RFA.
Although the letter of intent is not required, is not binding, does
not commit the sender to submit an application, and does not enter
into the review of subsequent applications, the information that it
contains allows NIAID staff to estimate the potential review workload
and to avoid conflict of interest in the review.  The letter of
intent is to be sent to Dr. Mark Rohrbaugh at the address listed
under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application
form PHS 398 (rev. 09/91).  Item 2a on the face page of the
application must be marked "Yes" and the RFA number and the words
"THE CAUSES AND CONSEQUENCES OF THYMUS INVOLUTION" must be typed in.
These application forms may be obtained from the institution's office
of sponsored research and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301)
496-7441.

Applications must be received by July 21, 1993.  Applications that
are not received from the applicant organization by the receipt date
or that do not conform to the instructions contained in PHS 398 (rev.
09/91) application kit, will be judged to be non-responsive and will
be returned to the applicant.

The RFA label available in the application form PHS 398 must be
affixed to the bottom of the face page.  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.  FIRST award
(R29) applications 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.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact, single-sided photocopies, in
one package to:

Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional exact copies of the grant
application and all five sets of appendix material must also be sent
to Dr. Mark Rohrbaugh at the address listed under INQUIRIES.

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 GCRC as a resource for conducting
the proposed research.  If so, letter of agreement from either the
GCRC Program Director or Principal Investigator should be included
with the application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
DRG and by NIAID staff for responsiveness.  Those judged to be
incomplete will be returned to the applicant without review.  Those
considered to be non-responsive will be either returned without
review or referred to the DRG as an unsolicited application, to be
scheduled for initial review at the next DRG review cycle.

Those applications that are complete and responsive may be subjected
to a triage by an NIAID peer review group to determine their
scientific merit relative to other applications received in response
to this RFA.  The NIAID will withdraw from competition those
applications judged to be non-competitive for award and will notify
the applicant and institutional business officials.

Those applications judged by the reviewers to be competitive for
award will be further reviewed for scientific and technical merit by
a review committee convened by the Division of Extramural Activities,
NIAID.  The second level of review will be provided by the National
Advisory Allergy and Infectious Diseases Council.

The factors to be considered in the evaluation of scientific merit of
each application will be those used by NIH in the review of research
project grant applications, including:  the originality, and
feasibility of the approach; the training, experience, and research
competence of the investigator(s); the adequacy of the experimental
design; the adequacy and suitability of the facilities; and the
adherence, whenever appropriate, to NIH guidelines concerning
adequate representation of women and minorities in clinical research.
The following factor does not influence the priority score, but is
nonetheless carefully considered by the initial review group:  the
appropriateness of the requested budget to the work proposed.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit, as determined by peer review, program needs and
balance, and the availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

Joseph F. Albright, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A22
Bethesda, MD  20892
Telephone:  (301) 496-7551
FAX:  (301) 402-2571

Direct inquiries regarding review issues, address the Letter of
Intent to, and mail the two copies of the application to:

Mark Rohrbaugh, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C22
Bethesda, MD  20892
Telephone:  (301) 496-8424
FAX:  (301) 402-2638

Direct inquiries regarding fiscal and administrative matters to:

Mr. Jeffrey Carow
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B29
Bethesda, MD  20892
Telephone:  (301) 496-7075

Applicants who use express mail or a courier service are advised to
follow the carrier's requirements for showing a street address.  The
address for the Solar Building is:

6003 Executive Boulevard
Rockville, MD 20852

Schedule

Letter of Intent Receipt Date:  April 1, 1993
Application Receipt Date:       July 21, 1993
Scientific Review Date:         October 1993
Advisory Council Date:          February 1994
Earliest Award Date:            April 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research.  Awards will be made under the authority of the Public
Health Service Act, Title III, Section 301 (Public Law 78-410, as
amended; 42 USC 241) and administered under PHS grants policies and
Federal Regulations 42 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

.

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