Full Text PA-97-076
NIH GUIDE, Volume 26, Number 24, July 25, 1997
PA NUMBER:  PA-97-076
P.T. 34

  Immune System Disorders 

The National Institutes of Health (NIH) invites applications for
studies of the early stages of lymphoid lineage commitment and
development from hematopoietic stem cells. Although much has been
learned in recent years to enhance understanding of the later stages
of T, B and natural killer (NK) cell development, definition of the
complex processes that regulate lymphoid lineage commitment and early
lymphoid progenitor cell differentiation requires expanded research
efforts. Work in this area is expected to provide basic information
needed for future applications to human immunodeficiency diseases,
autoimmune diseases, hematopoietic stem cell transplantation and gene
transfer therapy.
Each NIH PA addresses one or more of 22 Health Promotion and Disease
Prevention priority areas identified.  These areas can be found via
the WWW at URL:  http://www.crisny.org/health/us/health7.html
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) awards (R29).  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
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.
Circulating blood cells, including the B, T and NK cells of lymphoid
lineage, continuously turn over, and must be regenerated from
uncommitted, pluripotent hematopoietic stem cells, which are located
in fetal blood, umbilical cord blood and adult bone marrow. These
stem cells are capable of both self-renewal and differentiation along
complex pathways to generate the lymphoid, myeloid, monocyte,
erythroid and megakaryocyte lineages of mature, functional cells.
Although recent results have begun to define some of the critical
events in lymphopoiesis, much remains to be learned about the tightly
regulated combination of factors that direct the initial commitment
of hematopoietic stem cells to the lymphoid lineage, and the
subsequent events that determine which mature lymphoid lineage, B, T
or NK cell, is produced.
It is known that key decisions made during lymphopoiesis depend on a
multitude of signals derived from cell:cell interactions, soluble
factors, and the extracellular matrix within stromal
microenvironments at specialized sites of maturation. Inappropriate
signals at any stage during this process might result in defective
immune system development and the consequent loss of vital immune
functions. Recent progress in achieving successful stem cell
engraftment across histocompatibility barriers suggests that stem
cell transfer will become an increasingly utilized therapy for a
variety of conditions. Furthermore, the potential for genetic
manipulation of hematopoietic stem cells to correct immune defects
underscores the need to understand the mechanisms by which gene
expression is regulated during lymphopoiesis, in order to design
vectors for gene therapy that can be targeted for expression at
appropriate developmental stages in restricted cell lineages.
Identification of cytokines, receptors and signaling molecules
involved at distinct and critical stages of lymphocyte development
would allow production of therapeutic agents to enhance specific
lineage development or function.
Techniques for the isolation and characterization of human, non-human
primate and rodent hematopoietic stem cells and early lymphoid
progenitor cells are being defined, and certain markers that identify
stages in lymphoid lineage commitment have been described. It is
known that in some diseases, such as HIV infection, there is damage
to stem cells or their microenvironment that prevents normal
engraftment and differentiation. It is currently feasible to obtain a
more definitive understanding of lymphopoiesis using both in vitro
and in vivo approaches, and to use this information for stem cell
therapy in human disease.
Research Objectives and Scope
A more complete definition of the integral stages of early B, T and
NK cell development will increase our understanding of the genesis of
the immune system, and will provide critical information needed for
therapeutic intervention mediated by stem cell transplantation, gene
transfer or immunotherapy. Innovative, multidisciplinary approaches
that include molecular genetics, biochemistry, cell biology and whole
animal studies are encouraged. Examples of research areas of interest
include, but are not limited to:
o phenotypic markers of lymphoid progenitor cells at different stages
of development;
o cell:cell or cell:microenvironment interactions that are critical
for lymphopoiesis;
o the effect of defects in the stromal environment on the growth and
differentiation of stem cells, and methods to overcome or correct
these defects;
o the role of soluble molecules and their receptors in triggering or
suppressing lymphoid lineage differentiation;
o signal transduction pathways involved in key lymphoid
differentiation decisions;
o transcription factor regulation during lymphopoiesis; and
o interdependence of differentiation pathways for lymphoid lineage
See NIH Guide of March 18, 1994 for requirements for inclusion of
Women and Minorities in research.  It is available via the WWW at
URL: http://www.nih.gov/grants (select NIH Guide for Grants and
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 on the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Extramural Outreach and Information,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone (301) 710-0267, email:
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
also be typed in section 2.
The completed, signed original and five legible, single-sided copies
of the application must be sent or delivered to:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
R29 applications must include at least three (3) 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
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
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
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
Review Criteria
The five criteria to be used in the evaluation of grant applications
are listed below.
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
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.
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
Each sponsoring Institute/Center is identified below.  A staff
contact for electronic and telephone is listed and inquiries
regarding programmatic (research scope, eligibility and
responsiveness) issues are encouraged.  The opportunity to clarify
any issues or answer questions from potential applicants is welcome.
National Institute of Allergy and Infectious Diseases
Helen Quill, Ph.D.
Telephone: (301) 496-7551
Fax:       (301) 402-2571
EMAIL:      hq1t@nih.gov
National Institute on Aging
Dr. Anna M. McCormick
Telephone:      (301) 496-6402
Fax:            (301) 402-0010
EMAIL:          am38k@nih.gov
National Heart, Lung and Blood Institute
Dr. Alan Levine
Telephone:      (301) 435-0050
Fax:            (301) 480-0868
EMAIL:          al20y@nih.gov
National Institute of Diabetes and Digestive and Kidney Diseases
David G. Badman, Ph.D.
Telephone:      (301) 594-7717
Fax:            (301) 480-3510
EMAIL:          David_Badman@nih.gov
Research under this announcement will be supported under program
cited in the Catalog of Federal Assistance (CFDA).  The PHS portion
of the CFDA is available at URL:
http://odphp.osophs.dhhs.gov/cfda/index.htm.  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 Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

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