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.

项目总结 大约3%的儿童患有某种形式的神经发育障碍(NDDS)。近期 大规模测序研究已经确定了数百个与NDDS相关的基因，包括自闭症 谱系障碍(ASD)。即使当这些疾病的遗传基础已知时，分子 发病机制可能仍然难以捉摸。TCF20相关的神经发育障碍就是这样的情况 (TAND)，一种由高危自闭症基因突变引起的毁灭性神经发育障碍 TCF20.患有自闭症的儿童出现自闭症症状，以及智力障碍、共济失调、 低眼压和癫痫发作，但其发病机制和可逆性尚不清楚。TCF20表达式 在发育过程中增加，并持续到成年，这表明它的功能可能不受限制 到发育过程。此外，我们最近发现，TCF20调节KEY的表达 神经元基因，包括小鼠神经元中的许多活动依赖基因。这些结果激励着 验证Tcf20具有调节依赖活动的发育后功能的假设 调节Tand-Associate表型的信号通路。这一假设将通过以下方式进行检验 尖端神经科学技术与新的小鼠遗传工具相结合。的目标 这一建议是为了(1)确定介导TAND发病的分子和神经元通路， (2)确定TCF20在体内活性依赖的信号通路中的作用；(3)确定关键的 开发期间及以后TCF20需求的时间窗口。完成拟议的 这项研究将使PI能够阐明TAND背后的分子和神经元信号缺陷 症状，并确定各种神经行为表型的临界治疗窗口。 这些结果将成为旨在扭转这些赤字的未来研究的基础。此外， 这项研究提供了一个极好的机会来解决活动如何-- 在健康和疾病条件下，依赖的信号调节大脑的发育。被指导者 这一阶段的奖项将由世界著名的神经遗传学家胡达·佐格比博士共同指导 拥有一支由系统神经科学、基因工程、电生理、单细胞等领域的专家组成的熟练团队 贝勒医学院的分析和计算分析。一个全面的指导计划是 提议增加电生理记录和单细胞分析方面的培训，以及 通过手稿和赠款写作方面的培训、对受训者的建议以及 在贝勒医学院和德克萨斯州巨大的生物医学环境中的合作 医疗中心。这项培训将为PI过渡到独立的 顶尖研究机构的教员职位。