Role of POU4F1 in a Novel Form of Ataxia

POU4F1 在新型共济失调中的作用

基本信息

批准号：
10741382
负责人：
Samuele Giuseppe Marro
金额：
$ 21.93万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10741382
关键词：
3-Dimensional ATAC-seq Abnormal coordination Address Adult Affect Afferent Neurons Alleles Animal Model Ataxia Atrophic Biology Brain Cell Maintenance Cell model Cells Cerebral cortex Childhood Chromatin Clinical Clinical assessments Computational Technique Data Development Developmental Delay Disorders Diagnosis Disease Epigenetic Process Equilibrium Exhibits Fibroblasts Functional disorder Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Techniques Genetic Transcription Genotype Goals Health Care Costs Heterozygote Human Image Immunofluorescence Immunologic Impairment Individual Induced pluripotent stem cell derived neurons Inherited Spinocerebellar Degenerations Intellectual functioning disability Intellectual impairment Intention Tremor Learning Loss of Heterozygosity Mediating Microelectrodes Molecular Molecular Abnormality Molecular Genetics Morphology Movement Mus Muscle hypotonia Mutation Nervous System Neurodegenerative Disorders Neurologic Neuronal Differentiation Neurons Organoids POU Domain Pathogenicity Patients Peripheral Phenotype Play Procedures Production Property Records Reporting Role Sensory Specific qualifier value Speech Delay Synapses Syndrome Technology Testing Tissues Transcriptional Regulation Variant cell motility density differentiation protocol directed differentiation early onset exome sequencing experimental study fetal genome-wide human pluripotent stem cell improved in vitro Model induced pluripotent stem cell insight loss of function multidisciplinary mutant nervous system disorder neurogenesis neuron loss neuronal excitability neuronal survival novel overexpression patient registry programs stem cell model transcription factor transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Heterozygous, pathogenic variants in POU4F1 were recently reported by our group to cause a novel ataxia syndrome (Webb et al., 2021). This neurological disorder is characterized by childhood onset ataxia, intention tremor, and hypotonia, and affected individuals have global developmental delay with mildly impaired intellectual development and speech delay or learning difficulties. POU4F1, also known as BRN3A, encodes a class IV POU-domain containing transcription factor expressed in the developing and adult brain. Little is known about the role POU4F1 plays in neurogenesis, neuronal differentiation, and neuronal survival in human neurons. Therefore, we propose to use iPSC to generate cellular models of the human brain to interrogate the consequences of POU4F1 haploinsufficiency. Our specific aims in this proposal are to 1) determine transcriptional signatures, epigenetic status, and functional abnormalities resulting from POU4F1 haploinsufficiency in iPSC – derived neurons; 2) assess the impact of POU4F1 haploinsufficiency in a iPSC model of the developing brain using cortical organoids; and 3) create a patient registry for POU4F1-related ataxia and better define the clinical features of this newly identified disorder. Taken together, these studies will uncover the pathophysiology, disease mechanism, and clinical spectrum of disease of POU4F1-related ataxia and address fundamental questions of human neurodevelopmental biology.

项目概要/摘要我们小组最近报道 POU4F1 杂合致病性变异可引起新型共济失调综合征（Webb et al., 2021）。这种神经系统疾病的特点是儿童期发病的共济失调、意向性。震颤和肌张力低下，受影响的个体有轻度受损的整体发育迟缓智力发育和言语迟缓或学习困难 POU4F1，也称为 BRN3A，编码 a。 IV 类 POU 结构域含有在发育中和成人大脑中表达的转录因子。了解 POU4F1 在人类神经发生、神经元分化和神经元存活中的作用因此，我们建议使用 iPSC 生成人脑细胞模型来询问神经元。 POU4F1 单倍体不足的后果是：我们在本提案中的具体目标是 1) 确定 POU4F1 导致的转录特征、表观遗传状态和功能异常 iPSC 衍生神经元中的单倍体不足；2) 评估 iPSC 中 POU4F1 单倍体不足的影响使用皮质类器官发育中的大脑模型；3) 创建 POU4F1 相关患者注册表总而言之，这些研究将更好地定义这种新发现的疾病的临床特征。揭示 POU4F1 相关共济失调的病理生理学、疾病机制和临床疾病谱并解决人类神经发育生物学的基本问题。