Full Text PA-96-050
 
GENETICS OF PARKINSON'S DISEASE
 
NIH GUIDE, Volume 25, Number 14, May 3, 1996
 
PA NUMBER:  PA-96-050
 
P.T. 34

Keywords: 
  Genetics 
  Neuromuscular Disorders 

 
PURPOSE
 
In response to new basic and clinical developments in Parkinson's
disease research and the interest of related voluntary organizations,
the Senate Appropriations Subcommittee on Health in 1995 asked the
National Institute of Neurological Disorders and Stroke (NINDS) to
organize a conference to assess the progress made in Parkinson's
disease research, to identify new opportunities and goals, and to
plan a research agenda to coordinate and strengthen the cooperative
activities of the several NIH institutes supporting research relevant
to this disorder.  This meeting was held in August 1995 and, with
NINDS, was jointly sponsored by the National Institute on Aging, the
National Institute of Environmental Health Sciences, and the National
Institute of Mental Health.  For fiscal year 1996 the Senate
Appropriations Committee urged the NINDS to expand its initiatives in
areas of promise identified at the August Parkinson's research
conference.  This Program Announcement (PA) is one of several
responses to Congressional interest in this subject.
 
The principal objective of this PA is to stimulate research into
possible genetic factors in the causation of Parkinson's disease. It
is hoped that the results of these investigations will help to
elucidate the causes and pathogenesis of Parkinson's disease.
 
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 initiated national activity for setting priority areas.  This
PA, Genetics of Parkinson's Disease, 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) 783-3238).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign, for-profit and
non-profit, public and private organizations, 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 grants
(P01) 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 the 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.  Applications submitted in response to this announcement
will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.  All
applications will receive an assignment to the appropriate institute
in accordance with the extant Referral Guidelines.
 
FUNDS AVAILABLE
 
Applications will compete for all available extramural grant funds on
the basis of scientific merit as judged by peer review.
 
RESEARCH OBJECTIVES
 
Background
 
Parkinson's disease (PD) is a common and disabling progressive
neurodegenerative disorder characterized by tremor, rigidity,
bradykinesia, and loss of postural reflexes.  It affects some half
million Americans.  The pathology is a rather specific pattern of
neuronal degeneration associated with Lewy-body formation in the
substantia nigra and other regions of the brain. PD responds for a
time to medication but is a progressive disorder.  There is no
specific biological test for the diagnosis of PD.  Twin studies have
shown variable results and suggest that the genetics of this disorder
will prove to be complex.  Despite the importance and severity of PD
and despite many years of research, a cause has not been identified
and there is no means of preventing the disease and no proven
permanent cure.
 
Familial parkinsonism has been recognized recently to be more
frequent than was thought previously.  Some physicians state that it
is more prevalent in clinical practice than familial Alzheimer's
disease or familial amyotrophic lateral sclerosis (ALS).  The signs
and symptoms in familial cases of pure Parkinson's disease do not
seem to differ from sporadic cases. Familial parkinsonism is
heterogeneous in onset and course, and wide variations of expression
may occur within families.  Most cases of PD are apparently sporadic,
as with ALS and Alzheimer's disease where multiple gene loci have
been found.  There have been reported a growing list of small
multicase PD families and a few large possibly autosomal dominant PD
pedigrees.  Several families in which Parkinson's disease seems to be
inherited have been followed over successive generations.  Sharing
information on these families and subjecting the data to
sophisticated computer analysis could hasten the identification of a
genetic basis or predisposition in this disorder.
 
Through linkage and allele sharing analysis of special populations of
Parkinson's disease families, it may be possible to identify the gene
or genes that increase the risk for the disorder.  Special
populations would include families with many affected members,
families that are geographically restricted, those in which the
origin of the disorder in that family may be traced back to a single
individual, or those that have an early age of onset or unusual
severity.  Restricting the phenotype to be studied by eliminating
from analysis those members of a family who do not have typical
Parkinson's disease may enhance the opportunity to localize the gene.
Some large families show apparent autosomal dominant inheritance with
high penetrance.  In small multicase families, the inheritance
pattern is compatible with either autosomal dominance with reduced
penetrance or multifactorial inheritance.  The apparent paucity of
parental consanguinity indicates no recessive inheritance.
Anticipation and X-linked inheritance are not thought to be involved
in PD.
 
Findings which would be of considerable importance in this search
would be the location of a genetic marker, determination of the
probability of penetrance, determination of possible genetic
heterogeneity, and evidence of multifactorial inheritance with
environmental interaction.  Finding genetic factors determining
susceptibility to PD will enhance epidemiological studies and
possibly lead to identification of susceptible groups and of
significant risk factors.  The areas of genetic research discussed in
this section , however, are not intended to be comprehensive or
exclusionary.  Researchers responding to this PA are encouraged to
consider novel approaches of the broadest nature in approaching the
pathogenesis of this disease.
 
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 inquiries.  Program staff may also provide
additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (REV.  05/95) is to be
used in applying for these grants.  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.  FIRST (R29) award
applications must include at least three sealed letters of reference
attached to the face page of the original application. FIRST
applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.  In addition, the PA title, ("Genetics of Parkinson's
Disease" NS-96 ) should be typed on line 2 of the face page of the
application form and the yes box should 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 or express service)
 
REVIEW CONSIDERATIONS
 
Applications that are complete and responsive to the PA will be
evaluated for scientific and technical merit in accordance with the
review criteria stated below, by an appropriate peer review group.
As part of the initial merit review, all applications will receive a
written critique and undergo a streamlined (triage) review process in
which only those applications deemed to have the highest scientific
merit will be discussed, assigned a priority score, and receive a
second review by the National Advisory Council, where applicable.
 
REVIEW CRITERIA
 
Criteria for scientific/technical merit review of applications are
the following:
 
o Significance and originality of proposed research from a scientific
or technical standpoint;
 
o Qualifications and experience of the principal investigator and the
staff in areas specifically related to the questions under
investigation;
 
o Adequacy of the conceptual and technical framework for the
research, including evidence of familiarity with relevant research
literature and proposed techniques;
 
o Access to appropriate study population (s), specimens, and
equipment;
 
o Adequacy of plan to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plan for the recruitment and retention of subjects will also be
evaluated;
 
o Adequacy of the existing and proposed facilities and resources;
 
o Adequacy of the data analysis plan;
 
o Appropriateness of the proposed budget, staffing plan, and the time
frame in relation to the proposed project.
 
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:
 
o Scientific merit as determined during the peer review process and
availability of funds.
 
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
 
Direct inquiries regarding fiscal matters to:
 
Ms. Pat Driscoll
Grants Management Branch
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:  pd23n@nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance, 93.853 and 93.854 for Neurological Disorders and Stroke
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 people.
 
.

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