XENOBIOTICS AND CELL DEATH/INJURY IN NEURODEGENERATIVE DISEASE

Release Date:  January 29, 1999

PA NUMBER:  PAS-99-054

P.T.

National Institute of Environmental Health Sciences
National Institute on Aging
National Institute of Neurological Diseases and Stroke
National Institute of Mental Health

PURPOSE

The objective of this Program Announcement (PA) is to stimulate research on
the relative roles of environmental, endogenous neurochemical and genetic
factors in the cause of neurodegenerative diseases.  The results of these
investigations should help clarify the part xenobiotics play in the etiology
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, Xenobiotics and Cell
Death/Injury in Neurodegenerative Disease, is related to one or more of the
priority  areas. Potential applicants may obtain a copy of "Healthy People
2000" at http://www.crisny.org/health/us/health7.html.

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.

FUNDS AVAILABLE

The total estimated funds available for support of this Program Announcement
is $2,000,000 per year.  This level of expenditure is dependent on the type of
applications received and the high scientific quality of those applications.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project
grant (R01) award mechanism. Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant. The
total project period for an application submitted in response to this PA may
not exceed 5 years.

RESEARCH OBJECTIVES

Much of the previous research in neurodegenerative diseases and dysfunction
has focused on the underlying biological processes critical to disease
manifestation in the hopes of developing new treatments; however, the relative
roles of environmental, endogenous neurochemical and genetic factors in the
cause of neurodegenerative diseases remain unclear.  Several studies have
implicated these factors in Parkinson's disease (PD), Alzheimer's disease
(AD), and amyotrophic lateral sclerosis (ALS).  For example, it is not
understood whether differences in prevalence rates of Parkinson's disease in
various communities may be due to the differential distribution of a
hypothetical environmental toxicant or may be more frequent where a heritable
defect is more common.  Moreover, analytic epidemiological studies have varied
in case and control selection methodology and venues (e.g., clinics,
population bases, different countries) partly accounting for the disparate
conclusions reached by investigators.

Attempts are needed to understand the contribution of environmental exposure,
endogenous susceptibility factors, and increasing age in the etiopathology of
neurodegenerative disease and will require a concurrent advancement and
refinement of methodologies and sciences.  Of particular significance may be
those approaches that can be used across species from lower animals to humans. 
Such approaches permit a precise characterization in animal models of
alterations arising from defined environmental exposures which can serve as a
cogent guide to underlying cellular and molecular mechanisms.

This program announcement is issued to encourage and foster investigator-
initiated basic and applied research on the possible role of xenobiotics in
brain cell death and injury resulting in  neurodegenerative diseases. 
Consequently, the  participating Institutes are interested in supporting
research in (but not limited to) the following areas:

Development of biomarkers of preclinical disease to identify those at risk for
selected environmental toxicants, and to identify those who would benefit from
trials of possibly neuroprotective drugs.

Development of criteria to standardize techniques for the early diagnosis of
disease to enhance the reliability of clinical and epidemiological studies.

Development of clinical imaging technology to enhance diagnosis and examine
the efficacy of therapeutic intervention.

Epidemiological studies aimed at identifying specific agents and/or
combination of chemicals associated with an increased risk for
neurodegenerative disorders.  These studies may target populations already
characterized in terms of the incidence and risks for neurodegenerative
diseases (e.g., farmers with significant exposure to pesticides).

Development of models of low-level and/or chronic exposure to environmental
agents and synergistic chemical interactions leading to neuronal injury. 
These paradigms are more likely to reflect the pattern of exposure(s) and
development of neurodegeneration.

Studies using genetically modified, transgenics, and knockout animals to study
increased susceptibility to environmentally induced neurodegeneration and the
efficacy of therapeutic interventions.

Development of models (including toxicant-induced paradigms) for studying the
mechanism of formation and the role of Lewy body and Lewy body-like inclusions
(PD) as well as amyloid plaques (AD) in neurodegeneration.

Studies on the effect of aging on toxicant-induced neurodegeneration, since
aging is a risk factor for a number of neurodegenerative diseases.

Studies on the role of inflammatory processes in toxicant-induced
neurodegeneration.  Inflammation may be the process by which an acute exposure
to toxic agents could lead to chronic neurodegeneration.

Studies on neuronally-derived proteins such as à-synuclein (PD) and presenilin
(AD) and their potential roles in toxicant-induced neurodegeneration.

Studies examining xenobiotics' potential influence on programmed cell death,
neural plasticity, or other processes critical to the maintenance of neuronal
viability and function.

Studies on remediation of neuronal defects using strategies such as gene
therapy.

Applications that are collaborations between basic and clinical
neuroscientists and/or interdisciplinary in nature are encouraged.  Also, the
National Institute on Mental Health (NIMH) has particular interest in studies
in the following areas:  using genetically modified, transgenics, and knockout
animals as models of behavioral traits or phenotypes relevant to mental
disorders; and the development and validation of biomarkers and clinical
imaging technologies to enhance diagnosis, disease progression, and efficacy
of therapeutic intervention in mental disorders.

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 policy results from the NIH Revitalization Act of 1993 (Section
492B of Public Law 103-43).

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 in the NIH Guide for Grants and Contracts, Vol. 23,
No. 11, March 18, 1994 available on the web at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not94-105.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. This
policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at
the following URL address:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies 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.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained 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, email: GrantsInfo@nih.gov.  They may also be downloaded from the
internet at http://www.nih.gov/grants/forms.htm.

Applicants planning to submit an investigator-initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more
in direct costs for any year are advised that he or she must contact the
Institute or Center (IC) program staff before submitting the application,
i.e., as plans for the study are being developed.  The applicant must obtain
agreement from the IC staff that the IC will accept the application for
consideration for award.  Finally, the applicant must identify, in a cover
letter sent with the application, the staff member and Institute or Center who
agreed to accept assignment of the application.  Refer to the NIH Guide for
Grants and Contracts, March 20, 1998 at
http://www.nih.gov/grants/guide/notice-files/not98-030.html.

The title and number of the program announcement 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 five signed photocopies in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines. An appropriate scientific review group convened in accordance with
the standard NIH peer review procedures will evaluate applications for
scientific and technical merit. 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

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In the
written comments reviewers will be asked to discuss the following  aspects of
the application 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 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 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 technologies?

(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?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

The adequacy of plans to include both genders, minorities and their subgroups,
and children as  appropriate for the scientific goals of the research. Plans
for the recruitment and retention of subjects will also be evaluated.

The reasonableness of the proposed budget and duration in relation to the
proposed research.

The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.  The initial review group will also examine the
provisions for the protection of human subjects and the safety of the research
environment.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications. 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 are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.  Direct inquiries regarding programmatic
issues to:

Annette G. Kirshner, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Science
Box 12233, MD EC-23
Research Triangle Park, NC 27709
Telephone: (919) 541-0488
FAX: (919) 541-5064
Email: kirshner@niehs.nih.gov

Eugene J. Oliver, Ph.D.
Division of Stroke, Trauma and Neurodegenerative Disorders
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 806
Bethesda, MD  20892
Telephone:  (301) 496-5680
FAX: (301) 480-1080
Email:  eo11c@nih.gov

Bradley Wise, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  wiseb@exmur.nia.nih.gov

Linda Brady, Ph.D.
Preclinical and Clinical Therapeutics Research Branch
National Institute of Mental Health
5600 Fishers Lane, Room 11-97
Rockville, MD 20857
Telephone:  (301) 443-9875
FAX:  (301) 443-4822
Email: lb@helix.nih.gov

Direct inquiries regarding fiscal matters to:

Mr. David Mineo
Division of Extramural Research and Training
National Institute of Environmental Health Science
Box 12233, MD EC-22
Research Triangle Park, NC 27709
Telephone:  (919) 541-1373
FAX:  (919) 541-2860
Email: mineo@niehs.nih.gov

Pat Driscoll
Grants Management Branch
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 1004
Bethesda, MD 20892-9190
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email: pd23n@nih.gov

Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  joseph_ellis@nih.gov

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone: (301) 443-2805
FAX:  (301) 443-6885
Email: Diana_Trunnell@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.113, 93.866 93.854, 93.242.  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, and 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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