Full Text MH-97-001
 
INNOVATIVE APPROACHES FOR MICROSCOPIC TRACT-TRACING
 
NIH GUIDE, Volume 26, Number 2, January 17, 1997
 
RFA:  MH-97-001
 
P.T. 34

Keywords: 
  Nervous System 
  Electron Microscopy 
  Biological Resources 
  Disease Model 

 
National Institute of Mental Health
National Institute on Aging
 
Letter of Intent Receipt Date: April 15, 1997
Application Receipt Date: June 11, 1997
 
PURPOSE
 
The National Institute of Mental Health (NIMH) and the National
Institute on Aging (NIA) invite applications for grant support to
research and develop innovative tract-tracing approaches to study the
connectivity of the nervous system at the level of the light and/or
electron microscope.  Particularly encouraged are applications which
propose research and development of novel tract-tracing techniques to
be used in post-mortem human and animal tissue, especially
aldehyde-fixed tissue. All applications proposing research on
innovative tract-tracing approaches will, however, be considered
pertinent to this Request for Applications (RFA).
 
This RFA is issued in response to the need for better ways to
demonstrate neural connections in humans and in nonhuman animal
models.  Research and development of novel methods and/or reagents to
clearly, reproducibly, and rapidly trace distant connections at the
level of the light and/or electron microscope in post-mortem tissue
would represent a major advance in the understanding of normal and
pathological brain organization.  Among the opportunities that this
would make available would be direct comparisons of the detailed
connectivity of circuits that underlie important mental functions
across normal animals, aged animals, animal models of disease,
non-diseased humans and humans with mental disorders and age-related
nervous system disorders.  Moreover, the ability to trace connections
in aldehyde-fixed tissue would allow such methods to be used in
conjunction with a variety of other methods currently used to study
the microstructure of the brain.
 
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 RFA,
Innovative Approaches for Microscopic Tract-Tracing, is related to
the priority areas of mental health, mental disorders, and
age-related brain disorders. 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 20402-9325
(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 small grants (R03) from the
NIMH (for additional eligibility requirements for NIMH small grants,
see PAR-97-015, NIH Guide for Grants and Contracts, Vol. 25, No. 4,
December 6, 1996).
 
MECHANISM OF SUPPORT
 
This RFA will use the National Institutes of Health (NIH) research
project grant (R01) and small grant (R03).  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant. The total project period for an R01
grant application submitted in response to this RFA may not exceed
four years. An R03 grant application submitted in response to this
RFA, may request up to $50,000 per year (direct costs) for up to two
years and may include salary support for the principal investigator.
The anticipated award date is September 1997.
 
Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of an award will
vary also. This RFA is a one-time solicitation.  Future unsolicited
competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures.
 
Because the small grant has special eligibility requirements,
application formats, and review criteria, applicants are strongly
encouraged to consult with program staff listed under INQUIRIES and
obtain the appropriate additional announcements for that grant
mechanism.
 
FUNDS AVAILABLE
 
It is estimated that approximately $1,000,000 will be available for
research projects (R01) and small grants (R03) funded under this RFA.
It is expected that this will support eight to twelve such awards,
depending upon the mix of mechanisms.  This level of support is
dependent on the receipt of a sufficient number of applications of
high scientific merit. Although the financial plans of NIMH and NIA
include these proposed levels of support, awards made under this RFA
are contingent upon the availability of funds for this purpose.
 
RESEARCH OBJECTIVES
 
Background
 
Neural circuits form the neural substrate of the complex information
processing carried out in the brain in both health and illness.  Not
only does the function of the central nervous system depend upon the
connections that are made by its constituent neurons, but the
function of any given region of the brain depends upon the particular
connections that region has with other regions of the nervous system.
This tenet holds from the level of groups of neurons, such as a
cortical area or subcortical nucleus, all the way down to the level
of the individual neuron and even to the subcellular level.
 
Not surprisingly, much of contemporary understanding of brain
function, as well as the formulation of new hypotheses, is based on
knowledge regarding specific connections of particular brain regions
or neurons.  In the last 20 years, the development and use of a
variety of tracer substances (e.g., tritiated amino acids,
horseradish peroxidase, fluorescent dyes, dextrans, and biocytin),
approaches (e.g., histochemistry, immunolabeling, fluorescence
microscopy, and autoradiography) and reagents (e.g., diaminobenzidene
and tetramethylbenzidene) have produced explosions of new data and
insights.  Most tract-tracing approaches, however, require the
deposit of tract-tracing substances in vivo, and depend on axoplasmic
flow for their transport.  This mechanism renders difficult the use
of such methods in some areas of animal research, such as study of
brain connectivity early in development, and, of course, precludes
their use in humans.
 
There are very few tract-tracing approaches that can be applied to
post-mortem tissue, and these approaches have severe limitations such
as being capricious, extremely slow, or being able to demonstrate
connections only over very small distances.  Thus, despite the wealth
of knowledge that has accumulated regarding neural connectivity in a
variety of species, very little is known about the detailed
connections of the human brain.
 
The ability to demonstrate detailed distant neural connections in
human post-mortem tissue would permit direct comparison of the normal
connectional organization of the human brain with the vast literature
on neural connections obtained in animal models and would allow a
more critical evaluation of the relationship of animal models of
brain disorders to human disease. Obversely, this capacity would also
reveal the alterations of neural circuits associated with specific
pathologies, such as Alzheimer's Disease and other neurodegenerative
diseases, and would facilitate the development of better animal
models of these pathologies. This technique could also delineate
changes in neural circuits, including axonal degeneration, which are
seen in normal and pathological aging.  Since it is likely that
approaches capable of demonstrating neural connections in human
pos-mortem tissue would also work in non-human post-mortem tissue,
these tools would represent important additions to the arsenal of
techniques available to study connections in nonhuman species.
 
Experimental approaches and disciplinary perspectives brought to bear
on research proposed by applicants are unrestricted and may be
multidisciplinary or interdisciplinary.
 
The following are examples of some of the research topics that would
be relevant to this RFA:
 
o  identification and evaluation of molecules which rapidly diffuse
through lipids fixed in aldehydes, such as those aldehydes used to
fix human tissue;
 
o  development of procedures to visualize tract-tracing molecules in
aldehyde-fixed tissue;
 
o  evaluation of efficacy of novel tract-tracing methods across
different neural systems, across different species, and across
different ages;
 
o  studies of parameters limiting the uptake and/or movement of novel
agents along axons and diffusion between neural cells;
 
o  assessment of novel tract-tracing molecules to identify local
neural circuits as well as long distance neural connections;
 
o  structure-function models to predict the efficacy of specified
molecules to demonstrate connections in post-mortem timmue;
 
o  evaluation of the ability of novel tract-tracing molecules to
identify degenerating or dysfunctional axons in animal models of
neuronal degeneration;
 
o  evaluation of the compatibility of novel tract-tracing methods
with other commonly used methods of microstructural analysis, such as
immunolabeling or histochemical staining;
 
o  development of procedures to co-visualize novel tract-tracing
molecules with cell-specific markers in order to identify specific
neuronal populations and their connections.
 
These broad objectives are meant to be illustrative and are not
exclusive of other objectives appropriate to this RFA.
 
Since the purpose of this RFA is to stimulate research and
development of new tract-tracing approaches, an important aspect of
the proposed efforts is the manner in which these new approaches will
be evaluated and compared to existing approaches.  This evaluation
should be scientifically valid, objective, and as quantitative as
possible.  Scientific interaction among principal investigators
supported as a result of this RFA is encouraged.
 
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 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 have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
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.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by April 15, 1997, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.  Although a letter of intent
is not required, is not binding, and does not enter into the review
of a subsequent application, the information that it contains allows
NIMH and NIA staff to estimate the potential review workload and
avoid conflict of interest in the review.
 
The letter of intent is to be sent to:
 
Michael F. Huerta, Ph.D.
Division of Neuroscience and Behavioral Science
National Institute of Mental Health
Parklawn Building, Room 11-103
Rockville, MD  20857
Telephone:  (301) 443-3563
FAX:  (301) 443-1731
Email: mhuerta@helix.nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and from the Division of
Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910,
telephone (301) 435-0714, FAX (301) 480-0525, Email:
ASKNIH@ODROCKM1.OD.NIH.GOV.
 
Guidelines for NIMH small grants (R03) are available on the NIMH home
page (www.nimh.nih.gov) under research grants (PAR-97-015), the NIMH
FAX4U (301-443-4513), and or may be obtained from the NIMH program
director listed under INQUIRIES.
 
The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
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.  In addition, the RFA title and number, "MH-97-001;
Innovative Approaches for Microscopic Tract-Tracing", must be typed
in section 2 of the face page of the application form and the YES box
must be marked.
 
Submit a signed, typewritten original of the application, including
the Checklist, and three signed, photocopies, in one package to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight mail service)
 
At the time of submission, two additional copies of the application
must be sent to:
 
Henry J. Haigler, Sr., Ph.D.
Division of Extramural Activities
National Institute of Mental Health
Parklawn Building, Room 9C-08
Rockville, MD  20857
Telephone:  (301) 443-1340
FAX:  (301) 594-0702
Email: hhaigler@ngmsmtp.nimh.nih.gov
 
Applications must be received by June 11, 1997.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by the
DRG and for responsiveness by NIMH and NIA staff.  Incomplete and/or
non-responsive applications will be returned to the applicant without
further consideration.  Applications that are complete and responsive
to the RFA will be evaluated for scientific and technical merit by an
appropriate peer review group convened by NIMH in accordance with the
review criteria stated below.  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 will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory
council or board, when applicable.
 
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  likelihood that the work will advance the ability to demonstrate
neural connectivity;
 
o  appropriateness and adequacy of plans to evaluate tract-tracing
approaches developed under this RFA;
 
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.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.
 
AWARD CRITERIA
 
o  potential to advance the field;
o  scientific merit of the proposed research as determined by peer
review;
o  responsiveness to the purposes and objectives outlined in this
RFA;
o  availability of research funds;
o  programmatic priorities.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Michael F. Huerta, Ph.D.
Division of Neuroscience and Behavioral Science
National Institute of Mental Health
Parklawn Building, Room 11-103
Rockville, MD  20857
Telephone:  (301) 443-3563
FAX:  (301) 443-1731
Email:  mhuerta@helix.nih.gov
 
Bradley C. Wise, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C30 - MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  wiseb@gw.nia.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
Parklawn Building, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov
 
Joseph Ellis
Grants Management Officer
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212 - MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  ellisj@gw.nia.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.242 (NIMH) and 93.866 (NIA).  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.  Awards will be
administered under PHS grants policy as stated in the Public Health
Service Grants Policy Statement (April 1, 1994).
 
PHS strongly encourages all grant and contract recipients to provide
a smoke-free workplace and promote the nonuse 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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