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Genetic Susceptibility and Epigenetic Modulation in Levodopa Induced Dyskinesia

左旋多巴诱发的运动障碍的遗传易感性和表观遗传调节

基本信息

批准号：
8982823
负责人：
David Anthony Figge
金额：
$ 3.36万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-24 至 2018-08-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8982823
关键词：
Accounting Address Adverse effects Affect Age Animal Model Behavior Behavioral Biochemical Bioinformatics Brain Candidate Disease Gene Chronic Clinic Clinical Code Collaborations Competence Corpus striatum structure CpG Islands DNA DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases Data Data Set Development Disease Doctor of Philosophy Dopamine Dorsal Dose Dyskinetic syndrome Elderly Environment Epigenetic Process Foundations Future Gene Targeting Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genetic Variation Genomic Segment Goals Histone Acetylation Human Immediate-Early Genes Immunoprecipitation Individual Investigation Laboratories Lead Learning Levodopa Life MAP Kinase Gene Maintenance Medicine Memory Mentors Methods Methylation Modeling Modification Molecular Motor Movement Disorders N-Methyl-D-Aspartate Receptors Nature Nerve Degeneration Neurobiology Neuronal Plasticity Neurophysiology - biologic function Oral Outpatients Parkinson Disease Patients Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacological Treatment Pharmacotherapy Phase Phenotype Phosphorylation Physicians Population Predisposition Prevalence Prevention Process Rattus Research Research Design Risk Role Sampling Science Scientist Severity of illness Signal Transduction Site Solid Specific qualifier value Techniques Therapeutic Training Transcriptional Regulation United States Writing base bisulfite sequencing career cellular sensitization cohort demethylation design economic cost epigenetic regulation exome sequencing experience genetic effector genetic variant histone modification nervous system disorder novel strategies public health relevance response skills standard of care trait

项目摘要

DESCRIPTION (provided by applicant): 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.