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.

描述（由申请人提供）：本申请旨在为 David Figge 在其医学博士/博士培训的实验室阶段提供 F31 支持。该提案的科学重点是确定遗传影响在左旋多巴引起的运动障碍的易感性和维持中的作用。 (LID)，左旋多巴治疗帕金森病的一个重要不良反应很常见，已知 50% 的帕金森病患者在治疗 5 年后会出现严重的 LID。个体间的变异性，尽管包括年龄和疾病严重程度在内的多种因素对 LID 诱导有已知的影响，但使用在其他药物遗传学研究中已成功的“极端不一致”研究设计无法完全解释这种观察到的变异性。，但以前没有在 PD 中使用过，我们将在患有 PD 和 LID 的人类患者中寻找 LID 的重要遗传修饰因子。接下来，我们将确定 DNA 甲基化的改变是否是背侧纹状体细胞记忆长期变化的基础。使用 LID 大鼠模型，我们将进行简化代表性亚硫酸氢盐测序，以专门观察纹状体中细胞致敏后 CpG 岛甲基化的变化，我们将使用甲基化 DNA 免疫沉淀来评估与 LID 相关的候选基因。我们还将通过测序数据验证已识别的甲基化标记，并通过在该过程中阻断 DNA 甲基转移酶来进一步评估 DNA 甲基化的重要性。在大鼠模型中诱导 LID，以证明 LID 形成是否需要 DNA 甲基化。 David Figge 拟议的培训计划由项目导师 David Standaert 博士和合作者 Nita Limdi 博士和 Richard Myers 博士赞助。培训计划的目标是为 PI 提供作为医师科学家的成功职业生涯的坚实基础，通过提供基于临床和实验室的项目，同时专注于以疾病为导向的过程，这是理想的培训环境。对于任何随着分子信息成为治疗决策中护理标准的一部分，通过对科学和医学的双重理解，收集和解释这些遗传影响的能力对于这一过程至关重要。通过向 David 提供了解遗传学对神经系统疾病的临床影响的技能，将使他能够扩展我们对分子过程的理解和应用，以实现个性化患者治疗。培训计划中包括帮助 PI 的经验：1) 获得以下方面的能力。多种技术融合神经生物学和生物信息学，2) 与其他科学家合作，3) 开展假设驱动的研究，4) 以书面和口头形式呈现数据，5) 有效地将研究与临床结合起来，6) 负责任地进行研究。