Identification of Candidate Genes at the Synapse in Autism Spectrum Disorders

描述(由申请者提供)：本申请提供了一个职业发展计划，整合了人类遗传学、分子神经科学和发育行为儿科学(DBP)等领域。古普塔博士的职业目标是成为一名独立的研究员，将遗传学和神经生物学的专业知识结合起来，阐明自闭症谱系障碍(ASD)的病理生理学所涉及的神经系统。更全面地了解自闭症是如何发展的，不仅将为治疗设计提供见解，还将促进我们对人类认知的生物学基础的理解。她在宾夕法尼亚大学获得了神经科学博士学位，并在费城儿童医院和耶鲁大学医学院获得了DBP临床研究员学位。她在马修州立大学的实验室接受了罕见变异基因发现的博士后培训。马修州立大学是精神病学遗传学领域的领先者，医学博士。她将在突触生物学领域的先驱、医学博士皮埃特罗·德·卡米利的指导下，发展分子神经科学方面的专业知识。此外，一个由备受尊敬的科学家组成的顾问团队将提供科学和职业建议。该研究计划的目标是识别和表征ASD神经突触的候选基因。古普塔博士在一名ASD患者中发现Piccolo(PCLO)被染色体倒位切割后，发现它是一个候选基因。PCLO是突触前细胞骨架基质的主要成分，具有不同的功能结构域，与多种分子结合。它似乎在协调从活动区的突触小泡聚集到胞吐和内吞的一系列事件中起着关键作用。这是一个有趣的发现，因为一些ASD的候选基因，如NLGNs，NRXN1和SHANK3，正在神经突触聚集，这表明突触是一个受损的部位。随着候选基因名单的增加，全面分析患者突变的功能后果变得至关重要，以便开始揭开这种疾病的病理生理学。为此，本项目旨在：(1)表征指标病例中精确的遗传异常，(2)通过序列和CNV分析确定PCLO在更大患者群体中的参与程度，(3)表征PCLO患者突变的功能后果，以及(4)识别导致该疾病的其他突触基因。该计划是以PCLO为起点，追踪ASD背后的神经系统。古普塔博士招募了一批优秀的导师和顾问来指导实验的设计和实施以及结果的分析。他们将支持候选人制定独立研究计划。为了加深她对人类遗传学和突触生物学的理解，她已经制定了一项额外的教学和强化研讨会的计划。她将充分利用耶鲁儿童研究中心的资源，该中心是自闭症临床评估和研究的国际公认领先者。 公共卫生相关性：自闭症谱系障碍(ASD)具有很强的遗传性，神经突触被认为是ASD的损害部位。这项研究的目的是识别和表征与这种疾病相关的突触基因。其目的是阐明参与ASD病理生理学的神经系统，这将为靶向治疗的发展提供见解。

DESCRIPTION (provided by applicant): This application presents a career development program that integrates the fields of human genetics, molecular neuroscience, and developmental-behavioral pediatrics (DBP). Dr. Gupta's career goal is to become an independent investigator who combines expertise in genetics and neurobiology to elucidate the neural systems involved in the pathophysiology of autism spectrum disorders (ASDs). A fuller picture of how ASDs develop will not only provide insights into treatment design but also advance our understanding of the biological basis of human cognition. She completed a PhD in neuroscience at the University of Pennsylvania and a clinical fellowship in DBP at the Children's Hospital of Philadelphia and Yale University School of Medicine. She obtained postdoctoral training in rare variant gene discovery in the laboratory of Matthew State, MD, PhD, a leader in the field of psychiatric genetics. She will develop expertise in molecular neuroscience under the guidance of Pietro De Camilli, MD, a pioneer in the field of synaptic biology. In addition, an advisory team of highly-regarded scientists will provide scientific and career advice. The objective of the research plan is to identify and characterize candidate genes at the neural synapse for ASDs. Dr. Gupta identified Piccolo (PCLO) as a candidate gene when it was found to be transected by a chromosomal inversion in a patient with ASD. PCLO, a major component of the presynaptic cytoskeletal matrix, has diverse functional domains and binds a wide variety of molecules. It appears to have a key role in orchestrating the sequence of events from synaptic vesicle clustering at the active zone to exocytosis and endocytosis. It is an intriguing finding given that a number of candidate genes for ASD, such as the NLGNs, NRXN1, and SHANK3, are converging at the neural synapse, indicating that the synapse is a site of damage. As the list of candidate genes grows, it has become critical to comprehensively analyze the functional consequences of patient mutations in order to start unraveling the pathophysiology of the disorder. With that purpose, this project aims to: (1) characterize the precise genetic abnormalities in the index case, (2) determine the extent of PCLO's involvement in the larger patient population through sequence and CNV analysis, (3) characterize the functional consequences of patient mutations in PCLO, and (4) identify additional synaptic genes which contribute to the disorder. The plan is to use PCLO as a starting point to trace a neural system which underlies ASD. Dr. Gupta has recruited an outstanding group of mentors and advisors to guide the design and conduct of experiments and analysis of results. They will support the candidate as she develops an independent research program. She has formulated a plan for additional didactics and intensive workshops to deepen her understanding of human genetics and synaptic biology. She will take full advantage of the resources of the Yale Child Study Center, an internationally recognized leader in the clinical evaluation and research of ASDs. PUBLIC HEALTH RELEVANCE: Autism spectrum disorders (ASDs) are strongly genetic, and the neural synapse has been implicated as a site of damage in ASDs. This research aims to identify and characterize synaptic genes which are associated with the disorder. The goal is to elucidate the neural systems involved in the pathophysiology of ASDs, which will provide insights into the development of targeted treatments.