Full Text PA-95-090


NIH GUIDE, Volume 24, Number 33, September 22, 1995

PA NUMBER:  PA-95-090

P.T. 34

  Biology, Cellular 

National Institute on Deafness and Other Communication Disorders
National Institute on Aging


This program announcement reiterates the continuing interest of the
National Institute on Deafness and Other Communication Disorders
(NIDCD) and the National Institute on Aging (NIA) in receiving
applications for the study of the mechanisms that maintain,
terminate, and reinitiate the sequence of olfactory neurogenesis in
the olfactory epithelium throughout the life of the organism.  The
scope of this program announcement (PA) includes the neurogenic
sequence of cell proliferation, differentiation, synaptogenesis,
growth, migration, maturation, cell death, and the mitotic signals to
renew the cycle under both normal physiologic conditions and after
experimental procedures, such as olfactory nerve transection, that
perturb this unique cycle of neural development.  This PA is timely
because the recent development of molecular tools makes the
identification of specific types of sensory neurons and their
connections practical.  This announcement supplements a previous one,
Nasal Chemoreception: Regeneration and Trophic Interactions (NIH
Guide, Vol. 18, No. 34, September 29, 1989), and is part of the NIDCD
programmatic theme of sensory regeneration in the auditory,
vestibular, and chemosensory systems.


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,
Olfactory Neurogenesis, is related to the priority areas of diabetes
and chronic disabling conditions and special population objectives.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-11474-0 or Summary Report:  Stock No.
017-001-11473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).


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.
Applications from minority individuals, women, and individuals with
disabilities are encouraged.  Foreign institutions are not eligible
for First Independent Research Support and Transition (FIRST) (R29)


The support mechanisms for grants in this area will be the research
project grant (R01) and the FIRST (R29) award.


Olfactory sensory neurons are the only mammalian projection neurons
that are known to be continuously replaced during adult life.  These
neurons develop from precursor cells in the olfactory epithelium both
under normal physiologic conditions and after various experimental
procedures, such as chemical exposure and naris closure, that change
the rate of cell division.  These exceptional neurons can reestablish
functional synaptic connections with their target cells in the
olfactory bulb.  No other neuron retains its ability to grow from the
periphery into the central nervous system in adulthood.  This
suggests that olfactory sensory neurons must express the right
receptor molecules and match that expression to the right targets in
the olfactory bulb, not only during initial development, but also
during subsequent neurogenesis. These features provide a unique model
system for the study of certain aspects of neural development and
cell replacement in the adult animal.  In addition, recent studies of
neural development suggest that many neuronal precursors are
multipotent and ultimately adopt a neuronal fate on the basis of
local environmental factors.  It is possible that progenitors of
olfactory sensory neurons in the olfactory epithelium are
multipotent.  These progenitors might ultimately serve as a source of
neurons to replace neurons lost from other parts of the nervous
system as a result of aging, neurodegenerative diseases, and injury.

Many aspects of the cellular and molecular mechanisms of olfactory
neurogenesis need to be investigated, including the regulation of
gene expression, a process central to understanding neurogenesis.
Substantial  opportunities exist to address these issues through the
application of contemporary molecular biologic, molecular genetic,
and biotechnologic tools that make the identification of specific
types of receptor neurons and their connections practical.  Examples
of possible research topics are listed below.  Investigators are
encouraged to address these or other issues relevant to the
understanding of the cellular and molecular mechanisms of olfactory

o  Define the lineage of the olfactory sensory neuron.  Characterize
the olfactory stem cell and the intermediate cell forms in olfactory

o  Determine the role of macrophages in cell proliferation.
Determine how transcription factors control cell proliferation.

o  Characterize the mechanisms of cell signaling critical to the
determination of the fate of olfactory cells.

o  Investigate the mitogenic protein growth factors required for
genesis of neurons and of supporting cells in the olfactory
epithelium.  Investigate the trophic factors necessary for survival
of each of these types of cells.  Determine the relationship between
these two types of cells.

o  Search for tropic molecules that may be involved in olfactory axon
pathfinding.  Determine the role of glial cells in this pathfinding.

o  Identify the signals and response mechanism leading to cessation
of axonal growth and formation of a functional synapse.

o  Determine whether all or only some olfactory sensory neurons
undergo programmed cell death.  Characterize the mechanisms that
regulate any such apoptosis.  Identify the molecules associated with
apoptosis and with necrosis.

o  Determine how an equilibrium between cell birth and cell death is
maintained in the olfactory epithelium.  Identify the mechanisms of
upregulation and downregulation of cell birth and cell death.

o  Determine whether olfactory neuron precursors are multipotent.
Examine how the cell's environment influences the fate of olfactory
epithelial cells.

o  Characterize and identify mechanisms responsible for changes
occurring in olfactory neurogenesis as a function of age of the

o  Characterize and identify mechanisms of differential effectiveness
of specific trophic or growth factors in aging vs. developing

o  Characterize and identify mechanisms of aging-related altered
responsiveness of olfactory epithelium to injury or disease.

Novel approaches to address the cellular and molecular mechanisms of
olfactory neurogenesis are encouraged.  Examples of approaches that
can be used to study olfactory neurogenesis include, but are not
limited to, those below.

o  Retroviral techniques and specific dyes to label olfactory cell

o  Organotypic and cell culture models to characterize and manipulate
the cells, molecules, and genes that determine olfactory

o  Genetically modified cell lines and transgenic animals to permit
identification of factors and genes involved in olfactory

o  Cell transplants for the study of olfactory neurogenesis in the
developing and adult nervous system.


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 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 was reprinted in the Federal
Register of March 28, 1994 (FR 59 14508-14513) to correct typesetting
and errors in the earlier publication,  and reprinted in the NIH
GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994. 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.


Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available from most institutional offices of sponsored research and
may be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 6701 Rockledge Drive,
MSC 7762, Bethesda, MD 20892-7762, telephone (301) 435-0714, email:
girg@drgpo.drg.nih.gov.  The title and number of the program
announcement must be typed in Section 2 on the face page of the

Applications for the FIRST Award (R29) 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.

The completed original application and five legible copies must be
sent or delivered to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (express/courier service)


Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by an appropriate Initial Review Group within the
Division of Research Grants, NIH, in accordance with the standard NIH
peer review procedures. Following scientific-technical review, the
applications will receive a second-level review by the appropriate
national advisory council.

Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened 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 applications under review, will be discussed, assigned a priority
score, and receive a second level review by the appropriate national
advisory council or board.


Applications will compete for available funds with all other
applications assigned to that Institute.  The following will be
considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program priorities among research areas of the program


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

Direct inquiries regarding programmatic issues to:

Jack Pearl, Ph.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400-C
6120 Executive Boulevard MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301)-402-3464
FAX:  (301)-402-6251
Email:  Jack_Pearl@nih.gov

Judith A. Finkelstein, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 3C307
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301)496-9350
FAX:  (301)496-1494
Email:  FinkelsJ@gw.nia.nih.gov

Direct inquiries regarding fiscal matters to:

Sharon Hunt
Division of Extramural Activities
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400-B
6120 Executive Boulevard, MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-0909
FAX:  (301) 402-1758
Email:  SH79F@Nih.Gov

Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue, MSC-9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  EllisJ@gw.nia.nih.gov


This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.173 and 93.866.  Awards 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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