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