This application is for F31 support of David Figge during the laboratory phase of his MD/PhD training. The scientific focus of the proposal is to determine the contribution of genetic influences in the susceptibility and maintenance of levodopa induced dyskinesia (LID), an important adverse effect of levodopa treatment for Parkinson's disease. LID is common, developing in 50% of PD patients after 5 years of treatment. LID is known to have significant inter-individual variability and although a variety of factors, including age and severity of disease, have known effects on LID induction they are unable to fully explain this observed variability. Using a extreme discordant study design which has been successful in other pharmacogenetic studies, but not previously employed in PD, we will search for important genetic modifiers of LID in human patients with PD and LID. Next, we will determine whether alterations in DNA methylation underlie the long standing changes in cellular memory of the dorsal striatum seen in LID. Using a rat model of LID, we will conduct reduced representation bisulfite sequencing to specifically look at changes in CpG island methylation following cellular sensitization in the striatum. Using methylated DNA immunoprecipitation we will assess candidate genes that are relevant in LID and known to undergo dynamic DNA methylation in the brain. We will also verify identified methyl marks from our sequencing data. The importance of DNA methylation will be further assessed by blocking DNA methyltransferases during the induction of LID in rat models to demonstrate if DNA methylation is required for LID formation. The proposed training plan for David Figge is sponsored by project mentor, Dr. David Standaert, and collaborators, Dr. Nita Limdi and Dr. Richard Myers. The overall goal of the training plan is to provide the PI with a solid foundation for a successful career as a physician scientist. By providing a project that is based both in the clinic and laboratory, while focused on a disease oriented process, is the ideal training environment for any aspiring physician scientist. As molecular information becomes a part of the standard of care in treatment decisions, the ability to gather and interpret these genetic influences will be of pivotal importance. Physician scientists will be vital to this process throug their dual understanding of science and medicine. By providing David with the skills to understand the clinical influence of genetics on neurological disease will enable him to expand our understanding and application of molecular processes to personalize patient treatments. Included in the training plan are experiences that help the PI: 1) gain competence in a variety of techniques integrating neurobiology and bioinformatics, 2) collaborate with other scientists, 3) develop hypothesis-driven research, 4) present data in a written and oral format, 5) effectively integrate research with clinic, and 6) responsibly conduct research.
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that affects 3% of the population over age 65 and results in an economic cost to the United States of more than $25 billion dollars annually. Levodopa remains the most effective pharmacological therapy for PD but its use is limited by 'motor complications,' highlighted by dyskinesias. In this project, we will examine human genes that determine risk for levodopa-related dyskinesia, and fundamental mechanisms of memory involved in dyskinesia development providing important new approaches for the prevention and treatment of levodopa induced dyskinesia.
| A Figge, David; Standaert, David G (2017) Dysregulation of BET proteins in levodopa-induced dyskinesia. Neurobiol Dis 102:125-132 |
| Figge, David A; Standaert, David G (2016) SNPing SCNA regulatory elements gives a CRISPR view of genetic susceptibility in Parkinson's disease. Mov Disord 31:1479 |
| Figge, David A; Eskow Jaunarajs, Karen L; Standaert, David G (2016) Dynamic DNA Methylation Regulates Levodopa-Induced Dyskinesia. J Neurosci 36:6514-24 |
