The Role of Fox-1 in Neurodevelopment and Autistic Spectrum Disorder

描述（由申请人提供）：项目概述：自闭症谱系障碍（ASD）是一种神经发育疾病，由不同程度的社交、语言和行为障碍所定义，每150名儿童中就有1名受到影响。最严重的是自闭症。症状出现在儿童早期，并导致严重的终身残疾。自闭症有很强的遗传基础，但遗传学是复杂的，涉及多个基因和环境因素的贡献。了解这种疾病的病因对于改善临床治疗和诊断测试以及了解人类神经发育都很重要。在这方面，对导致自闭症的罕见突变的研究成为识别关键神经发育途径及其组成部分的有力手段。一个有趣的候选者是Fox-1基因（也称为A2BP1）。一些证据表明Fox-1是一个重要的神经发育因子。Fox-1是一种选择性剪接的神经元特异性调节因子，似乎在人和小鼠大脑的基因表达中发挥重要作用。此外，4名患者被鉴定出Fox-1基因突变和ASD特征，其中一名患者临床诊断为自闭症。我们假设Fox-1在人类早期神经发育的基因表达中起着关键作用，而这种破坏可能导致自闭症谱系障碍。为了验证这一点，我们将1)使用剪接微阵列平台在人类神经细胞中鉴定由Fox-1调控其选择性剪接的基因。接下来，我们将通过鉴定人类神经元细胞向神经元分化过程中发生的fox -1依赖性替代剪接变化，将这些发现扩展到神经发育。最后，我们将利用人类胎儿大脑的原位杂交技术表征这些Fox-1靶基因在神经发育中的作用，并作为合作项目的一部分，将其与小鼠发育联系起来。该项目将提高我们对神经发育过程中基因调控的理解，并促进自闭症和ASD的进一步研究。候选人对神经发育和神经退行性疾病有浓厚的兴趣，在分子生物学和RNA处理方面有扎实的背景，这将通过人类遗传学，功能基因组学和生物信息学方面的经验得到加强。该网站是一个富有成效的学术机构，拥有广泛的神经科学社区，致力于候选人的职业发展。导师是自闭症研究领域的领导者，拥有一个活跃的神经遗传学实验室，拥有遗传和分子研究的所有工具。总的来说，这些资源为候选人过渡到独立的科学研究者角色提供了最佳环境。相关性：自闭症谱系障碍被认为是美国的一个主要健康问题。据估计，多达50万儿童经历过某种形式的这种情况，其中可能有四分之一患有临床自闭症。自闭症和自闭症谱系障碍会对患者及其家庭造成毁灭性的影响，因为这种情况会导致严重的终身残疾。这里提出的研究，检查了大脑特异性基因表达调节器在神经发育中的作用，将扩展我们对导致ASD的原因的认识，最终可能有助于更好地治疗、预防，甚至有朝一日治愈自闭症。

DESCRIPTION (provided by applicant): Project Summary: Autistic spectrum disorder (ASD) is a neurodevelopmental condition defined by variable degrees of impairment in socialization, language, and behavior which affects one out of every 150 children. The most severe form is autism. Symptoms present early in childhood and cause significant lifelong disability. Autism has a strong hereditary basis but the genetics are complex, involving contributions from multiple genes as well as environmental factors. Understanding the etiology of this disease is important, both for improving clinical treatments and diagnostic testing, as well as for understanding human neurodevelopment. In this regard, the study of rare mutations which lead to autism becomes a powerful means of identifying critical neurodevelopmental pathways and identifying their components. One intriguing candidate is the Fox-1 gene (also called A2BP1). Several lines of evidence suggest that Fox-1 is an important neurodevelopmental factor. Fox-1 is a neuron-specific regulator of alternative splicing that appears to play a significant role in gene expression in both human and mouse brain. Furthermore, four patients have been identified with mutations in the Fox-1 gene and features of ASD, including one with a clinical diagnosis of autism. We hypothesize that Fox-1 plays a key role in gene expression during early human neurodevelopment and that disruptions can lead to autistic spectrum disorder. To verify this, we will 1) identify genes whose alternative splicing is regulated by Fox-1 in human neuronal cells using a splicing microarray platform. Next we will 2) extend these findings to neurodevelopment by identifying Fox-1-dependent alternative splicing changes that occur during the differentiation of human neuronal cells to neurons. Finally, we will 3) characterize the role of these Fox-1 target genes in neurodevelopment using in situ hybridization in human fetal brain and, as part of a collaborative project, correlate this to mouse development. This project will improve our understanding of gene regulation during neurodevelopment and stimulate further studies of autism and ASD. The candidate has a strong interest in neurodevelopmental and neurodegenerative disease as well as a solid background in molecular biology and RNA processing which will be strengthened by the experience in human genetics, functional genomics, and bioinformatics proposed here. The site is a productive academic institution, with an extensive neuroscience community, committed to the career development of the candidate. The mentor is a leader in the field of autism research and has an active neurogenetics laboratory with all the tools for genetic and molecular research. Overall, these resources provide the optimum environment for the candidate to transition into an independent role as a scientific investigator. Relevance: Autistic spectrum disorder is being recognized as a major US health concern. It is estimated that up to 500,000 children experience some form of this condition, with perhaps one-quarter having clinical autism. Autism and ASD can have a devastating impact on patients and their families as the condition leads to significant life-long disability. The studies proposed here, examining the role a brain-specific regulator of gene expression in neurodevelopment, will extend our knowledge of what can cause ASD and may ultimately help to better treat, prevent, or someday even cure autism.