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（NDDS）。最近的 大规模测序研究已经确定了数百种与NDD相关的基因，包括自闭症 频谱障碍（ASD）。即使已知这些疾病的遗传基础，分子也 发病机理可能仍然难以捉摸。 TCF20相关神经发育障碍就是这种情况 （TAND），一种由高风险自闭症基因突变引起的毁灭性神经发育障碍 TCF20。有tand的儿童出现ASD症状，以及智力残疾，共济失调， 低调和癫痫发作，但疾病的发病机理和可逆性尚不清楚。 TCF20表达 在发展过程中的增加并一直持续到成年，表明其功能可能不受限制 进行发展过程。此外，我们最近发现TCF20调节键的表达 神经元基因，包括小鼠神经元中许多活性依赖性基因。这些结果激励了 测试TCF20具有发达后功能以调节活动依赖性的假设 信号通路，介导了串联相关表型。该假设将使用 尖端的神经科学技术与新型小鼠遗传工具结合使用。目标的目标 该建议是（1）确定介导tand发病机理的分子和神经元途径 （2）确定TCF20体内活动依赖性信号通路的作用，（3）确定关键 在开发过程中和超越开发过程中，用于TCF20的时间窗口。拟议的完成 研究将使PI阐明tand的分子和神经元信号传导缺陷 症状，并确定各种神经行为类型的tand的关键治疗窗口。 这些结果将成为未来研究的基础，旨在扭转这些缺陷。此外， 这项研究提供了一个绝佳的机会，可以解决活动如何的基本问题 - 依赖信号在健康和疾病状况下调节大脑发育。指导 该奖项的阶段将由世界著名的神经遗传学家Huda Zoghbi博士指导 与系统神经科学，遗传工程，电湿莫洛（Electrophysiolo GY），单细胞的熟练专家团队 贝勒医学院的分析和计算分析。一个全面的指导计划是 提出的包括电生理记录和单细胞分析的其他培训，以及 通过手稿和赠款写作培训，对受训者的咨询和 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。该培训将为PI提供必要的技能，使其过渡到独立 顶级研究机构的教师职位。