Identifying Novel Targets for Pharmacological Intervention in Dystonia
Abstract
Dystonia is a debilitating movement disorder characterized by loss of voluntary control over motor movements and repetitive muscle contractions that detrimentally interfere with essential everyday functions. It frequently develops as a result of trauma, underlying neurological condition, or exposure to drugs. However, some forms of dystonia are also inherited and are caused by mutations in different genes. Currently, effective pharmacological treatments for dystonia are missing largely due to insufficient understanding of molecular underpinning of the events disrupted in the disease. Recent research increasingly points to the role played by the striatum, a major brain region that controls movements, in the pathology of dystonia. The genetic studies in human patients further suggest that imbalance in the neurotransmitter signaling to intracellular second messenger cAMP may be the key culprit in the disease. The central hypothesis of our research is that manipulating cAMP levels in the striatum may provide therapeutic benefit for dystonia. The research in this proposal addresses this hypothesis by seeking to identify novel druggable targets involved in regulating cAMP system in the striatum. We propose to conduct a genetic screen using genome modification and an innovative mouse model that allows imaging cAMP dynamics in native striatal neurons. This search for novel players will be conducted using state-of-the-art real-time imaging equipment and high-throughput robotic pipeline allowing parallel screening of several thousand genes. We expect that this unbiased and exploratory approach will lead not only to better understanding of molecular players involved in movement control but will also provide novel targets for drug development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910063
Entities
People
- Kirill A. Martemyanov
Organizations
- Scripps Research
- United States Army