Parkinson's disease susceptibility in carriers of lysosomal storage disorder genes

项目摘要/摘要 这份建议书描述了一项为期五年的有指导的实验室培训经验，旨在 研究神经退行性疾病遗传学的独立学术生涯。候选人两者兼备。 医学博士和博士学位，以及美国儿科委员会和美国儿科学会颁发的董事会证书 医学遗传学和基因组学委员会。申请者的职业目标是成为一名成功的领导者 医生-科学家进行独立资助的研究，继续为 神经退行性疾病遗传学领域。职业发展计划包括旨在 拓宽申请者的科学技能，包括(1)计算工具和大型统计分析 遗传数据集，(2)神经学表型特征/数据解释和(3)细胞方法 变体的功能验证。该计划还包括领导力、指导、赠款等方面的额外培训- 写作技巧和道德规范。有一段时间的指导研究培训，其中将包括技能获取， 随后是说教培训、研讨会、全国会议、咨询委员会和与导师的会议 通过向独立的过渡。这项拟议的研究旨在提高我们对基因的理解 帕金森病(PD)的基础和病理生理学研究 与溶酶体生物学相关的途径。有50多种溶酶体储存障碍(LSD)，它们是 导致溶酶体功能障碍的疾病。导致LSD高谢病的基因GBA的变异， 增加帕金森病的风险。其他LSD基因与帕金森病的关联还不太清楚。这个项目的总体目标是 项目是确定额外的LSD基因是否会增加帕金森病的风险，目的是改善帕金森病 诊断、风险预测和协助开发新疗法。申请人建议(1) 研究LSD患者的家庭以确定携带者中PD症状的频率，(2)分析 帕金森病患者和对照的大型遗传数据集，以评估LSD基因和帕金森病之间的关联，以及 (3)使用用于功能验证的细胞模型来测试LSD基因变体。这项五年计划将需要 主要在贝勒医学院(BCM)，这是一所拥有国家认可的院系的机构 遗传学和运动障碍，包括成熟的研究工作。美国商务部 BCM的分子和人类遗传学在培训早期研究人员方面有着长期的记录 非常成功的翻译研究人员。研究环境提供了最好的智力 环境和现有的最好的技术。这项建议提供了广泛的家庭研究经验- 基于表型特征、大型基因组数据集的分析以及变异体的功能验证 不确定的意义，拟议的职业发展计划将使该申请者准备成为一名 独立内科医生、科学家和神经退行性疾病遗传学领域的领导者。

Project Summary/Abstract This proposal describes a five year mentored laboratory training experience designed to lead to an independent academic career studying the genetics of neurodegenerative diseases. The candidate has both an M.D. and a Ph.D. as well as board certifications from the American Board of Pediatrics and the American Board of Medical Genetics and Genomics. The applicant’s career goal is to become a leading successful physician-scientist performing independently-funded research, continuing to make significant contributions to the field of neurodegenerative disease genetics. The career development plan includes training designed to broaden the applicant’s scientific skillset, including (1) computational tools and statistical analysis of large genetic datasets, (2) neurologic phenotypic characterization/data interpretation and (3) cellular approaches for functional validation of variants. This plan also incorporates additional training in leadership, mentorship, grant- writing skills, and ethics. There is a period of mentored research training which will include skills acquisition, didactic training, seminars, national meetings, an advisory committee and meetings with the mentor, followed by a transition to independence. The proposed research seeks to improve our understanding of the genetic underpinnings and pathophysiology of Parkinson’s disease (PD) by investigating a promising functional pathway related to lysosomal biology. There are over 50 lysosomal storage disorders (LSDs), which are diseases that result lysosomal dysfunction. Variants in GBA, the gene that causes the LSD Gaucher disease, increase the risk of PD. The associations of other LSD genes with PD are less clear. The overall goal of this project is to determine whether additional LSD genes increase risk of PD with the goals of improving PD diagnostics, risk prediction, and aiding in the development of novel therapies. The applicant proposes (1) studying families of individuals with LSDs to determine frequency of PD symptoms in carriers, (2) analyzing large genetic datasets of PD cases and controls to evaluate for associations between LSD genes and PD, and (3) testing LSD genetic variants using a cellular model for functional validation. This five year project will take place primarily at Baylor College of Medicine (BCM), an institution with nationally-recognized departments in both genetics and movement disorders, including well-established research efforts. The Department of Molecular and Human Genetics at BCM has a long track record of training early stage investigators to become highly successful translational researchers. The research environment provides the best intellectual environment and the best technology available. This proposal provides a broad research experience in family- based phenotypic characterization, analysis of large genomic datasets, and functional validation of variants of uncertain significance, and the proposed career development plan will prepare this applicant to become an independent physician-scientist and leader in the field of neurodegenerative disease genetics.