Full Text PA-96-071
 
DNA DAMAGE AND REPAIR IN CENTRAL NERVOUS SYSTEM INJURY
 
NIH GUIDE, Volume 25, Number 29, August 30, 1996
 
PA NUMBER:  PA-96-071
 
P.T. 34

Keywords: 
  Nervous System 
  Injury 
  Wound Healing 

 
National Institute of Neurological Disorders and Stroke
 
PURPOSE
 
The National Institute of Neurological Disorders and Stroke (NINDS),
invites applications for support of research that will increase our
knowledge of the genetic, molecular, cellular, and physiological
mechanisms of DNA injury and repair mechanisms in the nervous system
after ischemic and traumatic injury, and in neurodegenerative
disorders.
 
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 PA, DNA
Damage and Repair in CNS Injury, is related to the priority areas of
heart disease and stroke and unintentional injuries.  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 institutions,
for-profit and non-profit organizations, public or 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 and program project (P01)
grants.  Applications from minority institutions, minority
individuals, and women are particularly encouraged.
 
MECHANISM OF SUPPORT
 
The mechanisms of support for grants in this area will be the
investigator-initiated research project grant (R01), FIRST (R29)
award, and program project grant (P01). The principal investigator
will plan, direct, and, along with any co-investigators, perform the
research.  Applicants planning to submit a new (Type 1)
investigator-initiated grant application requesting $500,000 or more
in direct costs for any year must contact NINDS program staff before
submitting the application.  A cover letter that identifies the
program staff member who agrees to accept the assigned application
must be sent with the application.
 
RESEARCH OBJECTIVES
 
Background:  The basis of current knowledge and concepts of DNA
damage and repair are largely derived from non-neuronal cells/tissues
and non-mammalian research.  Therefore, a significant gap of
knowledge exists concerning the fundamental biochemical processes
that may lead to DNA damage and repair in the brain, and the
physiological relevance of such processes. There is evidence of DNA
damage in experimental stroke and trauma, and neurodegenerative
processes have been attributed to impairment in DNA repair
mechanisms.  Thus, DNA damage is a likely factor in promoting CNS
pathophysiology, and DNA repair may be an important mechanism for
maintenance of normal physiological function.  DNA damage and repair
are vibrant areas of research with broad implications for
understanding pathology in human disease and injury.  The application
of the science of DNA injury and repair may yield new and important
information on mechanisms of neuronal damage, and provide
opportunities for the development of novel and effective therapies to
reduce CNS injury in stroke, trauma, and neurodegenerative disorders.
 
The NINDS supports many basic and applied science programs focused on
understanding the biology of neurons and glia.  It is anticipated
that further progress in basic neurobiology will provide insight into
the inordinately complex molecular and cellular processes involved in
CNS ischemic and traumatic injury and repair.  Therefore, the intent
of this announcement is to encourage investigator-initiated
applications to study the mechanisms of DNA damage and repair in
cerebral ischemia and CNS trauma.
 
Research Goals and Scope:  Examples of investigator-initiated
research grant applications for basic, applied, and clinical studies
related to the understanding of DNA damage and repair mechanisms in
the CNS, may include, but should not necessarily be limited to:
 
o  Investigate the mechanisms of DNA damage and repair in neurons,
since our knowledge base, thus far, has been largely derived from
non-neuronal tissue (dividing cells);
 
o  Clarify the causal relationships between DNA damage and
pathological CNS responses to stroke and CNS trauma and
neurodegenerative disorders;
 
o  Explore the role of ICE, Bcl-2, p53, DNA pol b, bax and related
genes and gene families in DNA damage and repair in CNS injury and
neurodegenerative disorders;
 
o  Define critical events in pathological cascades resulting from DNA
damage such as trigger points or points at which reversible and
irreversible damage occurs;
 
o  Identify genomic locations of DNA damage and repair in neurons for
an accurate assessment of the biological importance of these lesions;
 
o  Assess the differences between potentially deficient
transcription-coupled repair and global repair mechanisms in
selective regions after CNS injury;
 
o  Identify genes, enzymes, and receptors associated with DNA repair
in neurons;
 
o  Assess the effects of DNA injury on the expression of trophic
factors involved in either development or regeneration after CNS
injury;
 
o  Identify the contribution of extracellular (e.g. NMDA, NO, pH,
Ca++) and intracellular (e.g. mitochondrial dysfunction, deacylation
of phospholipids) mechanisms to DNA damage and apoptosis in neurons;
 
o  Investigate the role of DNA injury and repair as mechanisms
underlying selective vulnerability, penumbra, pre-conditioning,
delayed cell death, and reperfusion injury in the CNS;
 
o  Examine the role of the DNA repair enzymes in cerebral injury from
stroke and trauma using transgenic animals with various defects of
nucleotide excision repair;
 
o  Assess the extent to which DNA damage and defective repair in
utero may compromise normal fetal development of the CNS;
 
o  Investigate the role of DNA repair mechanisms and responses of the
cerebral blood vessel wall cells following CNS ischemia and trauma.
Cerebrovascular responses are virtually unexplored and could provide
insight into the role of angiogenesis in CNS cell and tissue
survival;
 
o  Identify methods to measure DNA damage non-invasively in the brain
(e.g., SPECT, MRI).
 
Applicants are encouraged to develop and use new or refined
methodologies, instrumentation, and procedures that will reveal
mechanistic details of the CNS injury and reparative processes.
Basic, applied, or clinical studies to improve DNA damage and repair
control, prevent molecular pathophysiological changes, or restrain
cell death are welcome.
 
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.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) according to the instructions included in the
application package.  Applications 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 Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267,
email:  ASKNIH@odrockm1.od.nih.gov.  The title and number of the
program announcement must be typed in Section 2 on the face page of
the application.
 
The completed original application and five legible copies 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 (for courier service)
 
A number of other Institutes, Centers and Divisions (ICD) at the NIH
may be interested in the general subject of this program
announcement.  For example, the NINDS and the NIA have mutual
interest in understanding chronic neurodegenerative disorders such as
Alzheimer's Disease.  Applications submitted in response to this PA
that propose to do research in scientific areas that overlap ICD
interests will receive a funding component assignment in accord with
existing referral guidelines and procedures established by the
Division of Research Grants, NIH.
 
REVIEW CONSIDERATIONS
 
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.
 
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.
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 and the safety of the
research environment.
 
AWARD CRITERIA
 
The standard review criteria will be used to assess the scientific
merit of applications.  Applications will compete for available funds
with all other applications.  The following will be considered when
making funding decisions:
 
o  quality of the proposed projects as determined by peer review;
o  availability of funds; and o program balance among research areas.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Dr. Thomas P. Jacobs
Division of Stroke and Trauma
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8A13
Bethesda, MD  20892
Telephone:  (301) 496-4226
FAX:  (301) 480-1080
Email:  TJ12G@NIH.GOV
 
Dr. Mary Ellen Cheung
Division of Stroke and Trauma
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8A13
Bethesda, MD  20892
Telephone:  (301) 496-4226
FAX:  (301) 480-1080
Email:  MM108W@NIH.GOV
 
Direct inquiries regarding fiscal matters to:
 
Ms. Kathleen Howe
Division of Extramural Activities
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  KH52X@NIH.GOV
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalogue of Federal Domestic
Assistance, Number 93.853, Clinical Research Related to Neurological
Disorders, and 93.854, Biological Basis Research in the
Neurosciences.  Grants will be awarded under the authority of the
Public Health Service Act, Title IV, Section 301 (Public Law 78-410,
as amended:  42 USC 241) and administered under PHS grant policies
and Federal Regulations 42 CFR Part 52 and 45 CFR 74. This program is
not subject to Health Services Agency Review of the intergovernmental
review requirements of Executive Order 12372.
 
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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