Identification of Candidate Genes at the Synapse in Autism Spectrum Disorders

描述（由申请人提供）：本申请提出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）领域。古普塔博士的职业目标是成为一名独立的研究者，结合遗传学和神经生物学的专业知识，阐明自闭症谱系障碍（ASD）病理生理学所涉及的神经系统。更全面地了解ASD如何发展不仅可以为治疗设计提供见解，还可以促进我们对人类认知生物学基础的理解。她在宾夕法尼亚大学完成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临床研究金。她在精神遗传学领域的领导者马修·斯特（Matthew State）医学博士、博士的实验室接受了罕见变异基因发现方面的博士后培训。她将在突触生物学领域的先驱Pietro De Camilli博士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咨询团队将提供科学和职业建议。 该研究计划的目的是确定和表征ASD神经突触的候选基因。Gupta博士在一名ASD患者中发现Piccolo（PCLO）被染色体倒位横断时，将其确定为候选基因。PCLO是突触前细胞骨架基质的主要成分，具有多种功能结构域并结合多种分子。它似乎有一个关键的作用，在精心策划的事件序列，从突触囊泡聚集在活动区的胞吐和胞吞。这是一个有趣的发现，因为许多ASD的候选基因，如NLGN，NRXN1和SHANK3，都聚集在神经突触上，表明突触是损伤的部位。随着候选基因列表的增长，全面分析患者突变的功能后果以开始解开疾病的病理生理学变得至关重要。为此，该项目旨在：（1）表征索引病例中的精确遗传异常，（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中患者突变的功能后果，以及（4）鉴定导致该疾病的其他突触基因。该计划是使用PCLO作为起点来追踪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，指导实验的设计和进行以及结果的分析。他们将支持候选人，因为她开发一个独立的研究计划。她已经制定了一个计划，额外的教学和密集的研讨会，以加深她对人类遗传学和突触生物学的理解。她将充分利用耶鲁儿童研究中心的资源，该中心是国际公认的ASD临床评估和研究的领导者。

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.