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

项目总结/摘要 本建议书描述了一个为期五年的实验室指导培训经验， 研究神经退行性疾病遗传学的独立学术生涯。候选人两者都有 医学博士和博士以及美国儿科委员会和美国儿科学会的认证 医学遗传学和基因组学委员会。申请人的职业目标是成为一个领先的成功 从事独立资助研究的医生科学家，继续为 神经退行性疾病遗传学领域。职业发展计划包括培训， 拓宽申请人的科学技能，包括（1）计算工具和大型统计分析 遗传数据集，（2）神经表型表征/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， 写作技巧和道德有一段时间的指导研究培训，其中将包括技能的获得， 随后进行了教学培训、研讨会、全国会议、咨询委员会和与导师的会议 过渡到独立。这项拟议中的研究旨在提高我们对遗传学的理解。 帕金森病（PD）的基础和病理生理学，通过调查一个有前途的功能 与溶酶体生物学相关的途径。有超过50种溶酶体贮积症（LSD）， 导致溶酶体功能障碍的疾病。GBA的变异体，导致LSD戈谢病的基因， 增加PD的风险。其他LSD基因与PD的关联不太清楚。这个项目的总体目标是 该项目旨在确定额外的LSD基因是否会增加PD的风险，以改善PD 诊断，风险预测，并帮助开发新的疗法。申请人建议（1） 研究具有LSD的个体的家庭以确定携带者中PD症状的频率，（2）分析 PD病例和对照的大型遗传数据集，以评估LSD基因与PD之间的关联，以及 (3)使用细胞模型测试LSD遗传变异以进行功能验证。这个为期五年的项目将 主要在贝勒医学院（Baylor College of Medicine），这是一所拥有国家认可部门的机构， 遗传和运动障碍，包括成熟的研究工作。部 分子和人类遗传学在培养早期研究人员方面有着悠久的历史， 非常成功的翻译研究人员。研究环境提供了最好的智力 环境和最佳技术。这一建议提供了广泛的研究经验，在家庭- 基于表型表征，分析大型基因组数据集，并对 不确定的意义，和拟议的职业发展计划将准备这个申请人成为一个 神经退行性疾病遗传学领域的独立医生-科学家和领导者。

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.