The role of Tcf20 in activity-dependent inhibitory signaling and autism spectrum disorder pathogenesis

Tcf20 在活动依赖性抑制信号传导和自闭症谱系障碍发病机制中的作用

• 批准号: 10570031
• 负责人: Jian Zhou
• 金额: $ 12.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570031
• 关键词: Address; Adult; Animals; Ataxia; Award; Behavior; Behavioral; Behavioral Assay; Binding; Biological Assay; Brain; Cells; Cellular biology; Child; Chromatin; Clinical; Cognitive; Collaborations; Complex; Computer Analysis; DNA Binding; Data; Defect; Development; Developmental Process; Disease; Electrophysiology (science); Environment; Faculty; Foundations; Frequencies; Future; Gene Expression; Genes; Genetic; Genetic Engineering; Grant; Growth; Immediate-Early Genes; Impairment; Institution; Intellectual functioning disability; Label; Large-Scale Sequencing; Learning; LoxP-flanked allele; Manuscripts; Measures; Mediating; Medical center; Medicine; Mentors; Methyl-CpG-Binding Protein 2; Modeling; Molecular; Morphology; Mus; Muscle hypotonia; Mutation; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neurons; Neurosciences; Pathogenesis; Pathway interactions; Phase; Phenotype; Physiological; Play; Positioning Attribute; Proteins; Reporter; Reporting; Research; Role; Seizures; Shapes; Signal Pathway; Signal Transduction; Stimulus; Symptoms; System; Techniques; Testing; Texas; Therapeutic Intervention; Time; Training; Whole-Cell Recordings; Work; Writing; autism spectrum disorder; behavioral study; cell type; college; conditional knockout; disease-causing mutation; gamma-Aminobutyric Acid; gene induction; genome-wide; high risk; in vivo; inhibitory neuron; knock-down; loss of function mutation; mouse genetics; mouse model; nervous system disorder; neurobehavioral; neurodevelopment; neurogenetics; neurophysiology; neurotransmission; novel; postnatal; postsynaptic; programs; promoter; risk variant; single cell analysis; single nucleus RNA-sequencing; skills; social; synaptogenesis; tool; transcription factor

PROJECT SUMMARY Approximately 3% of children suffer from some form of neurodevelopmental disorders (NDDs). Recent large-scale sequencing studies have identified hundreds of genes associated with NDDs including autism spectrum disorder (ASD). Even when the genetic basis of these diseases is known, the molecular pathogenesis can remain elusive. Such is the case for TCF20-associated neurodevelopmental disorder (TAND), a devastating neurodevelopmental disorder caused by mutations in a high-risk autism gene TCF20. Children with TAND present with symptoms of ASD, as well as intellectual disability, ataxia, hypotonia, and seizures, yet the disease pathogenesis and reversibility are not known. Tcf20 expression increases during development and persists into adulthood, suggesting that its function may not be limited to developmental processes. Furthermore, we recently found that TCF20 regulates the expression of key neuronal genes, including many activity-dependent genes in mouse neurons. These results motivate testing the hypothesis that Tcf20 has a postdevelopmental function to regulate activity-dependent signaling pathways that mediate the TAND-associate phenotypes. This hypothesis will be tested using cutting-edge neuroscience techniques in combination with novel mouse genetic tools. The objectives of this proposal are to (1) determine the molecular and neuronal pathways that mediate TAND pathogenesis, (2) determine the role of TCF20 in activity-dependent signaling pathways in vivo, and (3) determine critical temporal windows for Tcf20 requirement during and beyond development. Completion of the proposed study will allow the PI to elucidate the molecular and neuronal signaling deficits underlying TAND symptoms, and determine the critical treatment window of various neurobehavioral pheno types of TAND. These results will serve as the foundation for future studies aimed to reverse these deficits. Furthermore, this study provides an excellent opportunity to address the fundamental question of how activity - dependent signaling regulates brain development under healthy and disease conditions. The mentored phase of this award will be mentored by the world renowned neurogeneticist Dr. Huda Zoghbi, together with a skilled team of experts in systems neuroscience, genetic engineering, electrophysiolo gy, single cell analysis, and computational analysis at Baylor College of Medicine. A comprehensive mentoring plan was proposed including additional training in electrophysiological recordings and single cell analysis, as well as professional development through training in manuscript and grant writing, advising of mentees, and collaborations within the tremendous biomedical environment at Baylor College of Medicine and Texas Medical Center. This training will provide the necessary skills for the PI to transition to an independent faculty position at a top research institution.

项目摘要 大约3%的儿童患有某种形式的神经发育障碍（NDD）。最近 大规模测序研究已经确定了数百个与包括自闭症在内的NDD相关的基因 谱系障碍（ASD）。即使这些疾病的遗传基础是已知的， 发病机理仍然是难以捉摸的。TCF 20相关的神经发育障碍就是这种情况。 （TAND），一种由高危自闭症基因突变引起的破坏性神经发育障碍 TCF 20。患有TAND的儿童表现出ASD的症状，以及智力残疾，共济失调， 张力减退和癫痫发作，但疾病的发病机制和可逆性尚不清楚。Tcf 20表达 在发育过程中增加，并持续到成年，这表明其功能可能不受限制 发展过程。此外，我们最近发现TCF 20调节关键基因的表达， 神经元基因，包括小鼠神经元中的许多活性依赖性基因。这些结果激励 测试Tcf 20具有调节活动依赖性的发育后功能的假设， 介导TAND相关表型的信号通路。该假设将通过以下方式进行检验： 尖端的神经科学技术与新颖的小鼠遗传工具相结合。的目标 该建议是（1）确定介导TAND发病机制的分子和神经元途径， (2)确定TCF 20在体内活性依赖性信号通路中的作用，以及（3）确定关键的 开发期间和之后Tcf 20要求的时间窗口。完成建议 研究将使PI能够阐明TAND背后的分子和神经元信号转导缺陷 症状，并确定TAND的各种神经行为表型的关键治疗窗口。 这些结果将作为未来研究的基础，旨在扭转这些赤字。此外，委员会认为， 这项研究提供了一个很好的机会，以解决如何活动的基本问题- 依赖性信号传导调节健康和疾病条件下的大脑发育。受指导者 该奖项的第一阶段将由世界著名的神经遗传学家Huda Zoghbi博士指导， 拥有系统神经科学、基因工程、电生理学戈伊、单细胞 分析和计算分析。一项全面的指导计划 建议增加电生理记录和单细胞分析方面的培训， 通过手稿和赠款写作培训，为学员提供咨询， 在贝勒医学院和得克萨斯州的巨大生物医学环境中的合作 医学中心该培训将为PI过渡到独立的PI提供必要的技能。 顶尖研究机构的教授职位