Identification of Candidate Genes at the Synapse in Autism Spectrum Disorders

自闭症谱系障碍突触候选基因的鉴定

• 批准号: 8305034
• 负责人: Abha Rani Gupta
• 金额: $ 16.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-19 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305034
• 关键词: Alleles; Behavioral; Binding; Biological; Biological Assay; Biology; Blood; Candidate Disease Gene; Child; Chromosome inversion; Chromosomes, Human, Pair 7; Clinical; Clinical Research; Cognition; Consensus; Copy Number Polymorphism; Data; Development; Disease; Doctor of Philosophy; Educational workshop; Emotions; Endocytosis; Etiology; Event; Exocytosis; Family; Fellowship; Frequencies; Functional disorder; Gene Cluster; Genes; Genetic; Genetic Heterogeneity; Goals; Human; Human Genetics; Individual; Knowledge; Laboratories; Language; Lead; Mentors; Mind; Missense Mutation; Molecular; Molecular Abnormality; Mutation; Neuraxis; Neurobiology; Neuropeptides; Neurosciences; Outcome; Pathway interactions; Patients; Pediatric Hospitals; Pediatrics; Pennsylvania; Pervasive Development Disorder; Phenotype; Philadelphia; Play; Population; Protein Binding; Proteins; Recruitment Activity; Research; Research Personnel; Resources; Role; Science; Scientist; Screening procedure; Signaling Molecule; Site; Social Interaction; Societies; Source; Specific qualifier value; Structure; Synapses; Synaptic Vesicles; System; Tertiary Protein Structure; Testing; Transcript; Universities; Variant; Work; abstracting; autism spectrum disorder; base; career; career development; design; disability; effective therapy; gene discovery; improved; indexing; innovation; insight; interest; medical schools; neurexophilin; patient population; post-doctoral training; presynaptic; programs; psychogenetics; public health relevance; relating to nervous system; research clinical testing; research study; segregation; therapy design

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.

描述（由申请人提供）：本申请提出了一个整合人类遗传学、分子神经科学和发育行为儿科 (DBP) 领域的职业发展计划。 Gupta 博士的职业目标是成为一名独立研究者，结合遗传学和神经生物学的专业知识，阐明与自闭症谱系障碍 (ASD) 病理生理学相关的神经系统。更全面地了解自闭症谱系障碍的发展过程不仅可以为治疗设计提供见解，还可以增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 临床奖学金。她在精神病遗传学领域的领军人物 Matthew State 医学博士、哲学博士的实验室获得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先驱 Pietro De Camilli 医学博士的指导下发展分子神经科学方面的专业知识。此外，由备受推崇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自闭症谱系障碍神经突触的候选基因。当 Gupta 博士发现 Piccolo (PCLO) 在自闭症谱系障碍 (ASD) 患者体内因染色体倒位而被横断时，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，具有多种功能域并结合多种分子。它似乎在协调从活性区突触小泡聚集到胞吐作用和内吞作用的事件序列中发挥着关键作用。这是一个有趣的发现，因为许多自闭症谱系障碍的候选基因，如 NLGN、NRXN1 和 SHANK3，都聚集在神经突触处，表明突触是一个损伤部位。随着候选基因列表的增加，全面分析患者突变的功能后果以开始阐明该疾病的病理生理学变得至关重要。为此，该项目旨在：(1) 表征指示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) 表征患者 PCLO 突变的功能后果，以及 (4) 识别导致该疾病的其他突触基因。该计划是使用 PCLO 作为起点来追踪 ASD 背后的神经系统。 Gupta 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分析。他们将支持候选人开发独立的研究项目。她制定了一项额外教学和强化研讨会的计划，以加深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自闭症谱系障碍临床评估和研究领域的领导者。 公共健康相关性：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 的损伤部位。这项研究旨在识别和表征与该疾病相关的突触基因。目标是阐明参与 ASD 病理生理学的神经系统，这将为开发靶向治疗提供见解。