STUDIES INTO THE CAUSES AND MECHANISMS OF DYSTONIA
 
RELEASE DATE:  August 27, 2002

PA NUMBER: PA-02-156

EXPIRATION DATE: August 31, 2005 unless reissued. 

National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov/)

National Eye Institute (NEI) 
 (http://www.nei.nih.gov)

National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov/)

National Institute on Deafness and Other Communication Disorders (NIDCD)
 (http://www.nidcd.nih.gov/)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
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 
 
Dystonia is defined clinically as involuntary, often sustained, co-
contraction of agonist and antagonist muscles causing abnormal and often 
painful postures or movements.  It is generally believed to be centrally 
mediated.  Dystonia occurs due to many different etiologies. Although the 
prevalence and disease burden of this group of disorders is not well known, 
it is estimated by some sources that this debilitating movement disorder 
affects over 500,000 individuals in the USA. Some forms of dystonia are 
associated with specific genetic and/or environmental risk factors, but the 
underlying pathophysiological pathways remain elusive.  The purpose of this 
program announcement is to solicit applications for new studies on the 
underlying causes of human dystonia, secondary consequences of these movement 
disorders, and potential therapeutic strategies for treating these 
conditions.  

RESEARCH OBJECTIVES

Dystonia is the third most common movement disorder.  Manifestations can be 
focal, including spasmodic torticollis (cervical dystonia), blepharospasm, 
spasmodic dysphonia, "writers cramp" and other task specific dystonias. 
Dystonia can also be generalized, leading to involuntary twisting of the 
limbs and trunk.  Dystonia is defined as "primary" when it occurs in 
isolation (without other neurologic or medical problems) or as "secondary" 
when it occurs in conjunction with other neurological diseases and/or 
environmental insults. Various pathophysiological mechanisms have been 
suggested to explain the variable onset of dystonia, including a childhood-
adolescent window of susceptibility, low penetrance within genetic subtypes, 
and multiple suspected environmental triggers.  Dystonia appears to be a 
centrally mediated dysregulation of movement resulting from abnormalities in 
discrete regions of the brain.  In some forms of familial dystonia, 
particular mutations have been identified, which provide additional insights 
into pathophysiological pathways.

Studies in the field of dystonia offer a number of unique perspectives and 
opportunities in neurology and neuroscience. For example, in many types of 
dystonia the condition appears to derive from dysfunction rather than 
degeneration of neurons. Additionally, the familial forms of the disorder for 
which genetic causes are known have low penetrance (around 30% for most).  
This suggests that therapies may be able to "reset" neurons to overcome the 
dysfunction, and/or that modulation of environmental factors may influence 
the time of onset and/or the severity of the disease.  Recent studies 
indicate that the neurophysiologic basis of dystonia may reflect aberrations 
of neuronal plasticity, critical in development and motor learning, and hence 
studies into the dystonias may offer a window into dynamic aspects of 
neuronal "learning".  Research in this complex set of diseases will require 
coordinated, expanded and informed efforts among neuroscientists, clinical 
neurologists, and rehabilitation therapists, with access to patient 
populations, clinical databases, and patient material.  Studies that address 
underlying commonalities among different types of dystonia on the genetic, 
cellular, and/or clinical level may be of particular value in pursuing some 
of these goals.

The following are typical of research areas targeted by this initiative:

o Identification of genetic factors and heritable mechanisms associated with 
dystonia, including new gene discovery, causes of variable penetrance, 
multigene interactions, and studies of other potential molecularly based 
disease-modifying factors
o Identification of proteins that interact with dystonia-related cellular 
factors (genes, proteins) and determination of their coordinated function
o Creation and characterization of animal models for studying the 
pathophysiological basis of dystonia, functional consequences, and potential 
therapeutic strategies
o Determination of the role of environmental factors in inducing 
cellular/neurophysiologic changes associated with dystonia and dystonia-
related proteins 
o Studies of abnormalities in both plasticity and motor learning mechanisms 
that are relevant to dystonias
o Development of improved diagnostic and prognostic techniques
o Studies into neurophysiological and imaging (e.g., fMRI and TMS) approaches 
o Studies into the epidemiology of primary and secondary dystonia
o Therapeutic strategies in primary and secondary dystonia including both 
pharmacological and non-pharmacological interventions 
o Studies into assistive devices, orthotics, and potential accommodations
o Studies into environmental risks that cause or exacerbate dystonia
o Studies into surgical interventions in dystonia
o Studies of non-motor components of dystonia
o Studies into the features of pain in dystonia, including how treating pain 
may affect the underlying disability
o Sensory components of dystonia including studies ranging from basic motor-
sensory circuitry to dystonia therapy
o Studies contrasting the different phenotypes of dystonia (e.g., causes, 
onset, trajectory, affected muscle groups, level of dysfunction, and other 
manifestations) in order to gain insight into the pathophysiological 
mechanisms 
o Studies into mechanisms, causes, and treatments of dystonia that occurs as 
a disabling, secondary symptom in neurological diseases such as Parkinson"s 
disease, Huntington"s disease, tardive dyskinesia/dystonia, and other 
disorders

MECHANISM(S) OF SUPPORT 

This Program Announcement will use the National Institutes of Health (NIH) 
research project grant (R01), exploratory developmental research grant (R21), 
and career development mechanisms (K series). Note that policies on these 
mechanisms may differ among the sponsoring Institutes, and they may not 
accept applications that do not conform to specific Institute guidelines.  
Please contact program staff for Institute specific guidelines, and see the 
Institute websites as listed below for further details.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project.

For general information on NINDS funding mechanisms see the guidelines at:
http://www.ninds.nih.gov/funding/grant_mechanisms.htm

For general information on NEI mechanisms see the guidelines at: 
http://www.nei.nih.gov/funding/index.htm

For general information on NICHD mechanisms see the guidelines at: 
http://www.nichd.nih.gov/funding/funding-mechs.htm

For general information on NIDCD mechanisms see the guidelines at: 
http://www.nidcd.nih.gov/funding/

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.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) 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
o Faith-based or community based organizations 

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.   

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 two 
areas:  scientific/research and financial or grants management issues.

o Direct your questions about scientific/research issues to:

Katrina Gwinn-Hardy, M.D.
Program Director, Neurogenetics Cluster
National Institute of Neurological Disorders and Stroke, NIH 
6001 Executive Blvd Room 2142, MSC 9525
Bethesda, MD  20892-9525
Telephone:  (301) 496-5745
FAX:  (301) 402-1501
Email:  gwinnk@ninds.nih.gov

Chyren Hunter, Ph.D.
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  (301) 402-0528
Email:  clh@nih.gov

Ralph M. Nitkin, Ph.D.
Program Director, Biological Sciences and Career Development
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 2A03, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 402-2242
FAX:  (301) 402-0832
Email:  rn21e@nih.gov 

Lana Shekim, Ph.D.
Program Director, Voice and Speech
Scientific Programs Branch, DER
National Institute on Deafness and Other Communication Disorders, NIH
6120 Executive Blvd, EPS-400-C MSC 7180
Bethesda MD 20892-7180
Telephone: (301) 402-0832 
Fax: (301) 402-6251
Email: shekiml@nidcd.nih.gov

o Direct your questions about financial or grants management matters to:

Kathleen A. Howe
Grants Management Branch
National Institute of Neurological Disorders and Stroke, NIH
6001 Executive Blvd., Rm. 3290, MSC 9537
Bethesda, MD  20892-9537 
Telephone:  (301)496-9231
Fax:        (301)402-0219
Email:   kh52x@nih.gov

William W. Darby
Grants Management Officer
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 496-5884
FAX:  (301) 496-9997
Email:  wwd@nei.nih.gov

Christopher Myers
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17H, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-6996
FAX:  (301) 480-4782
Email:  cm143g@nih.gov 

Sara Stone
Chief, Grants Management Branch
National Institute of Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400B, MSC 7180
Bethesda MD 20892-7180
Telephone: (301) 402-0909
FAX: (3010) 402-1758
Email: stones@nidcd.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Specific instructions for the R21 
and K mechanisms can be found on the appropriate Institute websites as 
listed above.  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 when such a 
plan is appropriate for the area of study. Contact the program official for 
discussion if needed.

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

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 (NINDS), 93.867 (NEI), 93.929 (NICHD), 
and 93.173 (NIDCD), 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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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