Research Funding in 2011

The ultimate goal of the DMRF Science Program is to support the discovery of improved therapies and a cure. To achieve this goal, the DMRF is dedicated to stimulating the field of dystonia research and supporting the collaborations and projects necessary to accelerate progress.

The DMRF is also devoted to attracting young, talented investigators who are becoming the next generation of leaders in dystonia research. In many cases, DMRF grant and fellowship awards are intended to help investigators gather enough preliminary data to make them eligible for much larger grants from agencies such as the National Institutes of Health.

The DMRF is proud to announce this year's exciting research projects, some of which are continuing from 2010. Each of these projects is meaningful because it addresses one or more of the core directions necessary to advance the field. These core directions include furthering our fundamental understanding of what dystonia is, uncovering the mechanisms in the nervous system that leads to symptoms, creating models of dystonia to use in experiments, and discovering targets for new and improved therapeutics designed specifically to treat dystonia.

Congratulations to this year's award recipients and infinite thanks to our supporters for making this research funding possible.

Grants

Identification of Novel Drug Targets for DYT1 Dystonia
BioFocus, DPI
Leiden, The Netherlands

This project is the first step toward the rational design of dystonia therapeutics by identifying new potential drug targets.

A Yeast Expression System to Uncover Fundamental Aspects of TorsinA Function
Jeffrey Brodsky, PhD
University of Pittsburgh
Pittsburgh, PA
Michal Zolkiewski, PhD
Kansas State University
Manhattan, KS

To clarify the role of torsinA, this project explores molecular differences between normal and mutated torsinA produced in common brewer's yeast.  This project unites the expertise of two established investigators and their labs.

Characterization of Neuronal and Non-Neuronal Forms of THAP1 Protein
Michelle Ehrlich, MD
Mount Sinai School of Medicine
New York, NY

Mutations in the THAP1 gene are associated with DYT6 dystonia, a form of early onset dystonia, and may be related to the more common focal dystonias as well. Dr. Ehrlich plans to learn more about the protein associated with this gene and the relationship between the mutated protein and symptoms of dystonia. 

How Does the DYT1 Dystonia Mutation Alter TorsinA Function?
Rose Goodchild, PhD
University of Tennessee
Knoxville, TN

Dr. Goodchild has discovered that the mutated form of the dystonia protein torsinA interacts with recently discovered proteins LAP1 and LULL1. She is exploring the role of this new protein in normal torsinA function.

Transgenic Rat Models for DYT1 dystonia
Kathrin Grundmann, MD
University of Tübingen
Tubingen, Germany

The goal of this project is to develop the first rat model of DYT1 dystonia which will offer new opportunities to study this form of the disorder.

Abundance and Cellular Localization of Wildtype and Mutant SGCE in Human Skin Fibroblasts and Induced Pluripotent Stem Cell-derived Neurons
Anne Grunewald, PhD
University of Lubeck
Lubeck, Germany   

Myoclonus dystonia is caused by mutations in the epsilon-sarcoglycan (SGCE) gene in about 25% of cases. This study seeks to clarify why only a percentage of individuals who inherit the gene manifest symptoms and the differences between the proteins associated with normal and mutant SGCE. This may help clarify penetrance patterns for additional dystonias.

Activity-dependent Synaptic Plasticity in Globus Pallidus of Dystonia Patients
William Hutchison, PhD
Toronto Western Hospital
Toronto, Ontario

Dr. Hutchison is investigating whether electrical stimulation can be used to "recalibrate" brain networks and allow it to "relearn" a movement task without producing dystonia symptoms. This original work is a first step toward developing treatments to target these specific mechanisms.

Dystonia Gene Discovery Through Autozygosity Mapping and Massively Parallel Sequencing
Michael Kruer, MD
Oregon Health & Science University
Portland, OR

This project seeks to identify previously unknown genetic causes of dystonia using novel comprehensive genetic screening. The findings from this work have the potential to significantly advance our understanding of dystonia at the molecular level and identify new mechanisms of dystonia.

Neurophysiological Study of Myoclonus Dystonia
Sabine Meunier, MD, PhD
National Institute of Health and Medical Research (INSERM)
Paris, France
John Rothwell, PhD
University College London
London, UK

Although the protein associated with the gene responsible for myoclonus dystonia is very common, it is not clear why mutations in this gene cause the jerks and spasms that are so apparent in patients. This study uses new methods of brain stimulation to learn more about how symptoms arise. The findings will provide clues toward new treatments.

To Investigate the Molecular Mechanism of DYT16 Dystonia
Rekha Patel, PhD
University of South Carolina
Columbia, SC

This proposal focuses on clarifying the characteristics of two newly identified mutations in the DYT16 dystonia gene. Dr. Patel will study the mechanisms by which the mutated proteins might contribute to dystonia.

Pathophysiological Role of the Cholinergic System in Animal Models of Dystonia
Angelika Richter, MD and Melanie Hamann, MD
Freie Universitat Berlin
Berlin, Germany

Drs. Richter and Hamann are investigating the role of the neurotransmitter acetylcholine in a hamster model of dystonia. These experiments are deepening our understanding of dystonia and providing
clues for drug design and development.

The C. elegans OOC-5 Protein as a Model for Understanding the Role of Torsins at the Nuclear Envelope
Lesilee Rose, PhD
University of California, Davis
Davis, CA

Recent studies suggest that torsinA has an important role in the membrane that surrounds the nucleus of the cell, the nuclear envelope.  Dr. Rose and her team are using a worm model to clarify what this role is and how torsinA functions in cells.
 
Understanding the Role of the Cerebellum in Dystonia
Vikram Shakkottai, MD
University of Michigan
Ann Arbor, MI

Dr. Shakkottai is attempting to clarify the role of an area of the brain controlling balance and movement, the cerebellum, in dystonia. If the cerebellum is shown to play a pivotal role in dystonia, this may suggest new strategies for treatment.

Pharmacological Assessment of Muscarinic Receptor Antagonist Potency and Selectivity
Vastrata, Ltd.
Corbridge, Northumberland UK

This project involves testing of drug and drug-like compounds that interact with specific receptors in the brain. These compounds are thought to have an impact on the way the brain controls movements. This study will provide us with basic information about the properties of these compounds and the likelihood of their success as a potential treatment option for patients with dystonia.

Clinical and Genetic Studies of African American Patients with Dystonia
Zbigniew Wszolek, MD
Mayo Clinic Jacksonville
Jacksonville, FL

Dr. Wszolek, inpartnership with Dr. Mark LeDoux, is studying the genetics of several African American families impacted by dystonia, hoping to identify new gene(s) associated with adult onset, focal dystonia. This study will expand what is know about the genetics of focal dystonias and is providing important outreach to dystonia-affected African American families in Southern Georgia and Northern Florida.

Characterization of Substrate Interactions with TorsinA
Li Zhu, PhD
Chinese Academy of Sciences
Beijing, China

The DYT1 dystonia mutation appears to disrupt the ability of torsinA to play a role in regulating interactions with other proteins within the cell.  In this proposal, the interaction between torsinA and other proteins will be characterized, and undiscovered torsinA partner proteins may be identified.  This work will help to further our understanding of the function of torsinA.

Fellowships

Optogenetic Manipulation of Striatal Fast Spiking Interneurons in vivo
Daniel Leventhal, MD
University of Michigan
Ann Arbor, MI

This research focuses on one cell type, called striatal fast-spiking interneurons (FSIs), which appear to be associated with various forms of dystonia by applying a revolutionary optogenetic technology. The experiments will provide important data on the role of FSIs in normal and abnormal states.

A Novel Nonhuman Model to Probe Postural Control and Plasticity
Simon Overduin, PhD
University of California
Berkeley, CA

This study proposes that dystonia is a malfunction of the brain’s ability to coordinate sequences of movements and postures. This research introduces a new reversible primate model of dystonia, one that may allow scientists to explore the brain’s ability to plan movements in the normal state and to rehabilitate muscle control in the diseased state.

Neuroanatomical Abnormalities in DYT1 Dystonia
Chang-hyun Song, DVM
Emory University
Atlanta, GA

Exactly which region of the brain is responsible for the abnormal signals associated with dystonia symptoms is a matter of intense recent debate in the neuroscience community.  To better understand how symptoms originate, Dr. Song is exploring the brains of DYT1 mutant mice for suspected anatomical defects in three main brain regions currently believed to be involved in dystonia.

Defining the Parameters of TorsinA Function in Neural Development
Lauren Tanabe, PhD
University of Michigan
Ann Arbor, MI

Dr. Tanabe is using a new mouse model to pinpoint when and how the dystonia protein torsinA is functioning during the formation of the nervous system in embryonic development.  She is also exploring the role of a related protein, torsinB, as possibly protecting the nervous system from the effects of mutant torsinA.