Full Text PA-96-058
 
MECHANISM OF CELL DEATH AND INJURY IN NEURODEGENERATIVE DISORDERS
 
NIH GUIDE, Volume 25, Number 19, June 14, 1996
 
PA NUMBER:  PA-96-058
 
P.T. 34

Keywords: 
  Neuroscience 
  Biology, Cellular 
  Injury 
  Aging/Gerontology 
  Genetics 

 
National Institute of Neurological Disorders and Stroke
National Institute on Aging
National Institute of Environmental Health Sciences
National Institute of Mental Health
 
PURPOSE
 
The principal objective of this Program Announcement (PA) is to
stimulate research on the basic mechanisms of neuronal cell death and
injury as they relate to neurodegenerative disorders.  The results of
these investigations are expected to help in elucidating the
pathogenesis of these diseases.
 
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,
Mechanism of Cell Death and Injury in Neurodegenerative Disorders, is
related to the priority area of chronic debilitating diseases.
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.
Foreign institutions are not eligible for program project (P01)
grants or First Independent Research Support and Transition (FIRST)
(R29) awards.  Racial/ethnic minority individuals, women, and persons
with disabilities are encouraged to apply as principal investigators.
 
MECHANISM OF SUPPORT
 
The mechanisms available for support of this PA are the National
Institutes of Health (NIH) research project (R01), program project
(P01), and FIRST (R29) award.  Responsibility for the planning,
direction, and execution of the proposed research project will be
solely that of the applicant.
 
Because the nature and scope of the research proposed in response to
this PA may vary, it is anticipated that the size of an award will
also vary.
 
RESEARCH OBJECTIVES
 
Background
 
An important theme in current neuroscience is the search for common
mechanisms underlying the destruction of particular cell groups that
are unique to individual neurodegenerative disorders.  The study of
one disorder frequently yields information about the others.  There
is much accumulating evidence that the regulation of programmed cell
death in the nervous system utilizes mechanisms and pathways which
are common to simple and complex organisms, to pathways expressed in
normal development, to responses to many modes of injury such as
trauma, ischemia, and environmental and biological agents, to
diseases of early and adult life, and to aging processes.  Further
progress depends on a broad-based research effort uniting basic and
clinical studies over a broad range of approaches.  Studies of the
interaction between environmental, metabolic, anatomical, and genetic
factors are important research directions.  Using newly developed
technologies, scientists from diverse fields and disciplines are in a
position to make significant progress in understanding the critical
issues raised by the neurodegenerative disorders and the mechanisms
of the selective vulnerability of cells of the central nervous
system.
 
Although the pathway of cell death may be common, these disorders are
associated with a variety of risk factors including genetic and
environmental events.  For example, familial amyotrophic lateral
sclerosis (FALS), familial Alzheimer's disease (FAD), and
Huntington's disease (HD) are autosomal dominant, age related,
genetic disorders.  Familial Parkinson's disease (PD) has been
reported in a few large possibly autosomal dominant Parkinson's
disease pedigrees.  Still, except for HD, most cases of these
disorders have not been shown to be of genetic origin.  Exogenous
agents including neuroleptic drugs used in the treatment of
schizophrenia can cause tardive dyskinesia with PD-like symptoms.
While the etiology of many neurodegenerative disorders is unknown,
the mechanisms by which the neurons die may be similar.
 
Neurodegenerative diseases occur when a significant proportion of
neurons die.  The cause of the selective vulnerability of these cells
is not known.  Implicated in this destruction as well as in
destruction of neurons following neuronal injury are oxidative stress
by free radical damage, defective energy metabolism, external or
internal toxins, genetic factors, and aging.  Altered regulation of
programmed cell death during development may be involved in the
etiology of specific mental disorders.  Alone or in combination,
these factors could lead to necrotic or apoptotic cell death.
 
Changes in mitochondrial function with age or injury can alter
cellular energetics, free radical metabolism, and vulnerability to
further harm.  Defects in energy metabolism at the mitochondrial
level may contribute to activation of excitatory amino acid receptors
which may then lead to calcium influx. Defects in energy metabolism
further impair intracellular calcium buffering.  A consequence of
increasing intracellular calcium is cell damage and death.  It is
also quite possible that oxidative stress itself may lead to damaged
mitochondrial DNA with subsequent further deterioration of
respiratory enzyme activities.  Previous work has demonstrated that
the MPTP toxicity, which mimics Parkinson's disease, involves
inhibition of complex 1 of the electron transport chain as well as
oxidative stress.  It has also been recently demonstrated that the
generation of nitric oxide appears to play a role in cell death in
the MPTP animal model.
 
Research is needed to develop and use novel cell culture techniques
and transgenic animal models to study the possible role of defective
organelles and aberrant metabolism in the pathophysiology of these
disorders.  Modern imaging techniques such as functional magnetic
resonance spectroscopy may be valuable in studying alterations in
metabolism caused by neuronal injury or degeneration.  Also, the
development of biochemical markers of oxidative stress in
cerebrospinal fluid, plasma and urine will help to assess directly
whether or not oxidative damage is a significant factor in these
disorders.
 
Metals are implicated in the etiology of a number of
neurodegenerative disorders.  Wilson's disease, for example, is a
systemic genetic disorder of copper metabolism and Hallervorden-Spatz
disease is characterized by deposits of melanin pigment containing
calcium and iron.  Studies of disease where metals play a role in
their pathogenesis may shed light on basic mechanisms leading to cell
destruction and death. Applications describing studies involving the
role of metals in various neurodegenerative disorders will be
considered responsive to this PA.
 
Neuronal apoptosis is a stereotypical pattern of changes associated
with cell death in response to a variety of insults. Major themes in
apoptosis research involve the critical regulators of terminal
apoptosis.  Those most clearly associated with this terminal process
are the pro-apoptotic and anti-apoptotic members of the bcl-2 family,
and the family of ICE-like cystine proteases that appear to be
required.  Much of what we know of these mechanisms is derived from
studies of simple organisms such as C. elegans and Drosophila and
further work in such systems is recognized as relevant to knowledge
of more complex organisms and thus responsive to this PA.
 
Work is needed to define patterns of expression of these gene
families in neurons, the determinants of those expression patterns,
the molecular mechanism(s) by which they regulate apoptosis, and
ultimately the development of strategies to mimic the anti-apoptotic
and inhibit the pro-apoptotic activity of the gene products.
 
Several pertubations of neurons lead ultimately to apoptosis. Some of
these require ongoing protein synthesis to lead to apoptosis, whereas
others do not.  Effort is needed to understand the genetic and
biochemical alterations that lead a cell ultimately to apoptosis in
response to various insults and pathologic processes.  Examples that
require such study are growth factor deprivation, oxidation stress,
and cellular toxins such as beta-amyloid.  These studies need to
provide, in addition to a description of alterations associated with
death, the use of strategies to determine the importance of such
alterations in the ultimate death of the cell.
 
Study is required to determine the range of trophic factors that act
on particular types of neurons, the physiological role of these
factors in the cells in the developing and adult animal, and the
pharmacological potential of the factors to both prevent death of the
cells and to maintain their function.  It is important to determine
the signal transduction pathways by which trophic factors block cell
death and enhance cell growth.  It will be important to develop drugs
which mimic or stimulate these pathways.
 
The purpose of this PA would be to increase existing knowledge by
stimulating research to investigate further the mechanisms of
neuronal cell death and injury as they may contribute to our
understanding of neurodegenerative disorders.  Related situations
such as cell death in development or response to diverse injury are
regarded as relevant and responsive.  As discussed above, important
areas of investigation would be on the roles of energy impairment,
excitotoxicity, oxidation stress, nitric oxide, metals, and calcium
in either apoptotic or necrotic cell death. Research focused on
normal and pathological neuronal apoptotic mechanisms including
genetic and biochemical alterations resulting from injury or
pathological processes is clearly relevant.  These areas, however,
are not intended to be comprehensive or exclusionary.  The
investigation of potential therapeutic approaches targeted at
rescuing or slowing the decline of the injured or degenerating
neurons is also warranted.  Researchers responding to this PA are
encouraged to consider novel approaches of the broadest nature in
approaching the pathogenesis of these diseases.
 
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 sub populations 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 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 population, and
concerning the inclusion of minorities in study populations), which
have been in effect since 1990.  The current 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 INQUIRES.  Program staff may also provide
additional relevant information concerning the policy.
 
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 Office of
Extramural Outreach and Information Resources, National Institute 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.
 
FIRST (R29) award applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST award applications submitted without the required
number of reference letters will be considered incomplete and will be
returned without review.  In addition, the PA title and number
(Mechanism of Cell Death and Injury in Neurodegenerative Disorders
PA-96-053) must be typed on line 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/express service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established PHS
referral guidelines.  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 subjects and the safety of the research
environment.
 
AWARD CRITERIA
 
The following criteria will be considered in making a funding
decision:
 
Applications will compete for available funds with all other approved
applications assigned to these Institutes.  The following will be
considered in making funding decisions:  Quality of the proposed
project as determined by peer review, availability of funds, and
program priority.
 
INQUIRIES
 
Inquiries concerning this PA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Inquiries regarding programmatic issues may be directed to:
 
Eugene J. Oliver, Ph.D.
Division of Demyelinating, Atrophic, and Dementing Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 806
7550 Wisconsin Avenue
Bethesda, MD  20892-9150
Telephone:  (301) 496-1431
FAX:  (301) 402-2060
Email:  eo11c@nih.gov
 
Annette Kirshner, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
Building 3, P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-0488
FAX:  (919) 541-2843
Email:  kirshner@niehs.nih.gov
 
Neil Buckholtz, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Room 3C307
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  Bckholn@gw.nia.nih.gov
 
Douglas L. Meinecke, Ph.D.
Division of Neuroscience and Behavioral Science
National institute of Mental Health
5600 Fishers Lane (Rm. 11C-06)
Rockville, MD  20857
Telephone:  (301) 443-5288
FAX:  (301) 443-4822
Email:  dmein@helix.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Pat Driscoll
Division of Extramural Activities
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
7550 Wisconsin Avenue
Bethesda, MD  20892-9190
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  driscolp@nswide.ninds.nih.gov
 
Mr. David Mineo
Grants Management Branch
National Institute of Environmental Health Sciences
Building 2, P. O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-7628
FAX:  (919) 541-2860
Email:  mineo@niehs.nih.gov
 
Ms. Crystal Ferguson
Grants Management Office
National Institute on Aging
Gateway Building, Room 2N212
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  fergusonc@gw.nia.nih.gov
 
Ms. Diana Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C08
Rockville, MD  20857
Telephone:  (301) 443-3065
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.242 for Mental Health Research Grants, 93.853 and
93.854 for Neurological Disorders Grants, 93.113 for Environmental
Health Grants, and 93.866 for Aging grants.  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 to 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.
 
.

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