PATHOGENESIS AND TREATMENT OF DYSKINESIAS IN PARKINSON"S DISEASE
RELEASE DATE: July 18, 2002
PA NUMBER: PAS 02-129
EXPIRATION DATE: November 2, 2005, unless reissued.
National Institute of Neurological Disorders and Stroke (NINDS)
(http://www.ninds.nih.gov)
THIS PA CONTAINS THE FOLLOWING INFORMATION
o Purpose of the PA
o Research Objectives
o Research Scope
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS PA
With this Program Announcement, the National Institute of Neurological
Disorders and Stroke (NINDS) invites research grant applications (R01) that
address the development and treatment of dopamine-induced dyskinesias, a
major complication of current pharmacotherapy of Parkinson"s disease. The
purpose of this initiative is to 1) support the study of the pathophysiologic
basis of dopamine-induced dyskinesias, and 2) support the study of non-
dopaminergic pharmacologic agents for the treatment of dopamine-induced
dyskinesias.
RESEARCH OBJECTIVES
Dyskinesias constitute an important complication of the treatment of
Parkinson"s disease (PD). Soon after the recognition that loss of
dopaminergic neurons in the substantia nigra is the primary pathophysiologic
finding in PD the strategy of dopamine replacement by administration of its
precursor, levodopa, quickly became the standard therapy for PD. However,
more than half of all patients treated with levodopa or other dopaminergic
agonists will subsequently develop dyskinesias after approximately five
years. In many cases these treatment-induced complications limit the amount
of drug that can be administered and, as a further result, the amount of
symptomatic relief that can be obtained.
The clinical presentation of dyskinesias may vary significantly. These
abnormal, involuntary movements may be choreic or dystonic, they are
heterogeneous with respect to affected body part and may be associated with
other motor symptoms, and they may be associated with high, low or
intermediate blood levels of dopamine. When severe or painful, they limit
therapy but when mild they can be well tolerated by patients. However even
when mild, it is widely held that the appearance of dyskinesias foreshadows
the development of other, more disabling motor complications. Therefore,
even mild dyskinesias may lead the treating physician to reduce dopaminergic
therapy at the price of increased rigidity for the patient.
The pathogenesis of dyskinesias is poorly understood. In several areas the
available data are incomplete or in conflict. For instance, dyskinesias may
be induced by either dopaminergic agonists or antagonists (levodopa induced
or tardive dyskinesias, respectively) and can reflect low or high
concentrations of dopamine (dystonia and chorea, respectively). While it is
well established that dopamine-induced dyskinesias typically develop after
the sustained pulsatile administration of a dopamine agonist to a subject
(human or primate) with a significant nigral dopaminergic deficit such as in
PD, it is clear that dyskinesias can also develop in subjects with intact
nigral dopaminergic systems.
Our understanding of the physiologic basis of dopamine-induced dyskinesias is
similarly incomplete. According to the current model of the basal ganglia,
dopamine-induced dyskinesias should be associated with a particular pattern
of altered neuronal firing in the globus pallidus (internal and external
segments) and the subthalamic nucleus, however several indirect measures of
neuronal activity indicate the opposite pattern. Similarly, lesions in the
globus pallidus affect dyskinesias in the opposite pattern than would be
predicted by the standard model. Finally, much remains to be learned about
the physiologic substrate (the specific neurons and their firing patterns)
underlying the induction and resolution of dyskinesias.
While PD is conventionally considered a disorder of nigral dopaminergic
neurons, the integrated unit of cerebral cortex, basal ganglia and thalamus
that is compromised includes many neurotransmitters and neuromodulators.
These include glutamate, acetylcholine, adenosine, serotonin, opioids,
cannabinoids and their cognate receptors and subtypes. Many of these are
specifically associated with pathways that may be up or down regulated in PD
and thereby present the opportunity for non-dopaminergic approaches to the
therapy of PD and its complications.
RESEARCH SCOPE
Dyskinesias constitute an important complication of PD in three ways. First,
they are intrinsically disabling, second, they limit the symptomatic
management of the majority of advanced patients, and third, they highlight
the limitations of our current understanding of basal ganglia structure and
function. There is a particular need to investigate the pathogenesis,
pathophysiology and treatment of dyskinesias in PD patients and primate
models. Accordingly, applications are solicited to study the following
aspects of dyskinesias in the context of PD:
Pathogenesis and pathophysiology
o Physiological and functional imaging studies in MPTP-treated primates
followed by molecular neuroanatomy to establish the altered circuitry of
dyskinesia.
o Intraoperative recordings from humans during surgery to alleviate
dyskinesias.
Treatment
o Pre-clinical studies of non-dopaminergic agents in dyskinetic primates,
o Development and validation of clinical tools such as a dyskinesia rating
scale or a predictor of motor complications*,
o Pilot studies of non-dopaminergic agents in dyskinetic Parkinsonian
patients*.
*It is expected that such studies will also conform to the NINDS Pilot
clinical trial grant program announcement (PAR 01 119,
http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html) and such
studies should be submitted under the auspices of
PAR 01-119. Potential applicants should be aware that this PAR includes
additional review criteria and accordingly, are strongly encouraged to
contact NINDS program staff for guidance.
In summary, a systematic review of the literature indicates that a set of
focused studies on dyskinesias in PD should be undertaken. There is a need
to investigate the pathogenesis, pathophysiology and treatment of dyskinesias
in PD patients and primate models. The research plan must be soundly
developed in the context of the current knowledge/research base, with well-
defined and clear objectives. Applicants should elaborate on innovative
aspects of the proposed research and special attributes of the resources and
environment.
MECHANISM OF SUPPORT
This PA will use the NIH R01 award mechanism. As an applicant, you will be
solely responsible for planning, directing, and executing the proposed
project.
This PA uses just-in-time concepts. It also uses the modular as well as the
non-modular budgeting formats (see
http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if
you are submitting an application with direct costs in each year of $250,000
or less, use the modular format. Otherwise follow the instructions for non-
modular research grant applications.
At this time, it is not known if this PA will be reissued. Any future
unsolicited competing continuation applications based on this project will
compete with all NIH investigator-initiated applications and be reviewed
according to the customary peer review procedures.
FUNDS AVAILABLE
The NINDS intends to commit approximately $2,400,000 to fund up to 6 new
competitive grants in response to this PA over the course of the next three
years. Because the nature and scope of the proposed research will vary from
application to application, it is anticipated that the size and duration of
each award will also vary. Awards pursuant to this PA are contingent upon
the availability of funds and the receipt of a sufficient number of
meritorious applications.
ELIGIBLE INSTITUTIONS
You may submit application if your institution has any of the following
characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
As discussed above (RESEARCH SCOPE), some clinical studies responsive to this
PA will be expected to be submitted under the auspices of the NINDS Pilot
clinical trial grant program announcement (PAR 01 119,
http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html). Since such
applications must conform to the intent of both program announcements,
including the additional review criteria of PAR-01-119, potential applicants
are strongly encouraged to contact NINDS program staff for guidance.
WHERE TO SEND INQUIRIES
We encourage your inquiries concerning this PA and welcome the opportunity to
answer questions from potential applicants. Inquiries may fall into three
areas: scientific/research, peer review, and financial or grants management
issues:
o Direct your questions about scientific/research issues to:
Paul Sheehy, Ph.D.
Program Director
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Rm 2214
6001 Executive Blvd MSC 9525
Bethesda, MD 20892-9525
Phone: 301-496-5680
FAX: 301-480-1080
Email: sheehyp@ninds.nih.gov
o Direct your questions about financial or grants management matters to:
Chris Ann Davis
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Suite 3290
6001 Executive Blvd MSC 9537
Bethesda, MD 20892-9537
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: davisc@ninds.nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). The PHS 398 is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 435-0714,
Email: GrantsInfo@nih.gov.
APPLICATION RECEIPT DATES: Applications submitted in response to this program
announcement will be accepted at the standard application deadlines, which
are available at http://grants.nih.gov/grants/dates.htm. Application
deadlines are also indicated in the PHS 398 application kit.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications
requesting up to $250,000 per year in direct costs must be submitted in a
modular grant format. The modular grant format simplifies the preparation of
the budget in these applications by limiting the level of budgetary detail.
Applicants request direct costs in $25,000 modules. Section C of the
research grant application instructions for the PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step
guidance for preparing modular grants. Additional information on modular
grants is available at
http://grants.nih.gov/grants/funding/modular/modular.htm.
SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:
Applications requesting $500,000 or more in direct costs for any year must
include a cover letter identifying the NIH staff member within one of NIH
institutes or centers who has agreed to accept assignment of the application.
Applicants requesting more than $500,000 must carry out the following steps:
1) Contact the IC program staff at least 6 weeks before submitting the
application, i.e., as you are developing plans for the study,
2) Obtain agreement from the IC staff that the IC will accept your
application for consideration for award, and,
3) Identify, in a cover letter sent with the application, the staff member
and IC who agreed to accept assignment of the application.
This policy applies to all investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended or revised
version of these grant application types. Additional information on this
policy is available in the NIH Guide for Grants and Contracts, October 19,
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.
SENDING AN APPLICATION TO THE NIH: 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)
APPLICATION PROCESSING: Applications must be received by or mailed on or
before the receipt dates described at
http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will
not accept any application in response to this PA that is essentially the
same as one currently pending initial review unless the applicant withdraws
the pending application. The CSR will not accept any application that is
essentially the same as one already reviewed. This does not preclude the
submission of a substantial revision of an application already reviewed, but
such application must include an Introduction addressing the previous
critique.
PEER REVIEW PROCESS
Applications submitted for this PA 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
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific
and technical merit.
As part of the initial merit review, all applications will:
o Receive a written critique
o Undergo a selection process in which only those applications deemed to have
the highest scientific merit, generally the top half of applications under
review, will be discussed and assigned a priority score
o 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 your application in order to judge the likelihood that the
proposed research will have a substantial impact on the pursuit of these
goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria
in assigning your application"s overall score, weighting them as appropriate
for each application. Your 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, you 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 your study address an important problem? If the aims
of your application are achieved, how do they advance scientific knowledge?
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? Do you acknowledge potential problem areas and consider alternative
tactics?
(3) INNOVATION: Does your project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does your project challenge
existing paradigms or develop new methodologies or technologies?
(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out
this work? Is the work proposed appropriate to your experience level as the
principal investigator and to that of other researchers (if any)?
(5) ENVIRONMENT: Does the scientific environment in which your 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?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your
application will also be reviewed with respect to the following:
PROTECTIONS: 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.
INCLUSION: The adequacy of plans to include subjects from both genders, all
racial and ethnic groups (and subgroups), and children as appropriate for the
scientific goals of the research. Plans for the recruitment and retention of
subjects will also be evaluated. (See Inclusion Criteria included in the
section on Federal Citations, below)
DATA SHARING: The adequacy of the proposed plan to share data.
BUDGET: The reasonableness of the proposed budget and the requested period
of support in relation to the proposed research.
OTHER REVIEW CRITERIA: As discussed above (RESEARCH SCOPE), some clinical
studies responsive to this PA will be expected to be submitted under the
auspices of the NINDS Pilot clinical trial grant program announcement
(PAR 01 119, http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html).
Since such applications must conform to the intent of both program announcements,
including the additional review criteria of PAR-01-119, potential applicants
are strongly encouraged to contact NINDS program staff for guidance.
AWARD CRITERIA
Applications submitted in response to a PA will compete for available funds
with all other recommended applications. The following will be considered in
making funding decisions:
o Scientific merit of the proposed project as determined by peer review
o Availability of funds
o Relevance to program priorities
REQUIRED FEDERAL CITATIONS
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components
involving Phase I and II clinical trials must include provisions for
assessment of patient eligibility and status, rigorous data management,
quality assurance, and auditing procedures. In addition, it is NIH policy
that all clinical trials require data and safety monitoring, with the method
and degree of monitoring being commensurate with the risks (NIH Policy for
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12,
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a
clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research - Amended, October, 2001," published in the NIH Guide for Grants and
Contracts on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a
complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research, updated racial and ethnic categories in compliance with the new OMB
standards, clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398, and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a)
all applications or proposals and/or protocols must provide a description of
plans to conduct analyses, as appropriate, to address differences by
sex/gender and/or racial/ethnic groups, including subgroups if applicable,
and b) investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
The NIH maintains a policy 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 is available at
http://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject participants for
all investigators submitting NIH proposals for research involving human
subjects. You will find this policy announcement in the NIH Guide for Grants
and Contracts Announcement, dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on
hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only
research using hESC lines that are registered in the NIH Human Embryonic Stem
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).
It is the responsibility of the applicant to provide the official NIH
identifier(s)for the hESC line(s)to be used in the proposed research.
Applications that do not provide this information will be returned without
review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a
project that is supported in whole or in part with Federal funds and (2)
cited publicly and officially by a Federal agency in support of an action
that has the force and effect of law (i.e., a regulation) may be accessed
through FOIA. It is important for applicants to understand the basic scope
of this amendment. NIH has provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the
application. In addition, applicants should think about how to structure
informed consent statements and other human subjects procedures given the
potential for wider use of data collected under this award.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals
for NIH funding must be self-contained within specified page limitations.
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs)
should not be used to provide information necessary to the review because
reviewers are under no obligation to view the Internet sites. Furthermore,
we caution reviewers that their anonymity may be compromised when they
directly access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of "Healthy
People 2010," a PHS-led national activity for setting priority areas. This PA
is related to one or more of the priority areas. Potential applicants may
obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance No. 93.853, and is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review. Awards are made under authorization of Sections 301
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
administered under NIH grants policies described at
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations
42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and discourage the 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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