Cellular and Molecular Analysis of the Psychiatric Risk Gene Transcription Factor 4 (TCF4)

精神病风险基因转录因子 4 (TCF4) 的细胞和分子分析

基本信息

批准号：
10407468
负责人：
BRADY J MAHER
金额：
$ 63.61万
依托单位：
LIEBER INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-02 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407468
关键词：
Adult Animal Model Anxiety Attentional deficit Award Behavior Behavioral Biological Assay Biological Models Biological Process Biology Brain Brain Diseases Caring Cell Differentiation process Cell model Cells Cellular biology ChIP-seq Child Childhood Chronic Clinical Complex Data Development Developmental Process Diagnosis Disease Disease model Electrophysiology (science)Epilepsy Etiology Family Functional disorder Gene Expression Profile Genes Genetic Genetic Heterogeneity Goals Grant Human Human Genetics Image In Vitro Intellectual functioning disability Knock-out Knowledge Lead Mental Depression Modeling Molecular Molecular Analysis Mus Mutate Mutation Myelin Neuraxis Neurobiology Neurons Oligodendroglia Outcome PF4 Gene Pathway interactions Patients Pharmacology Pharmacotherapy Phenotype Physiological Physiology Pitt-Hopkins syndrome Psychiatry Public Health Regulation Research Risk Role Sleep Disorders Socialization Symptoms Syndrome Therapeutic Intervention Translating autism spectrum disorder autosomal dominant mutation causal variant cell fate specification communication behavior comorbidity design disease phenotype disease-causing mutation experimental study functional improvement gene function genetic variant human model in vitro Model induced pluripotent stem cell insight migration mouse model mutant myelination neuron development neuropsychiatric disorder novel novel therapeutics oligodendrocyte lineage oligodendrocyte precursor postnatal precursor cell predictive signature programs relating to nervous system risk variant therapeutic target transcription factor transcriptome sequencing viral rescue

Adult Animal Model Anxiety Attentional deficit Award Behavior Behavioral Biological Assay Biological Models Biological Process Biology Brain Brain Diseases Caring Cell Differentiation process Cell model Cells Cellular biology ChIP-seq Child Childhood Chronic Clinical Complex Data Development Developmental Process Diagnosis Disease Disease model Electrophysiology (science)Epilepsy Etiology Family Functional disorder Gene Expression Profile Genes Genetic Genetic Heterogeneity Goals Grant Human Human Genetics Image In Vitro Intellectual functioning disability Knock-out Knowledge Lead Mental Depression Modeling Molecular Molecular Analysis Mus Mutate Mutation Myelin Neuraxis Neurobiology Neurons Oligodendroglia Outcome PF4 Gene Pathway interactions Patients Pharmacology Pharmacotherapy Phenotype Physiological Physiology Pitt-Hopkins syndrome Psychiatry Public Health Regulation Research Risk Role Sleep Disorders Socialization Symptoms Syndrome Therapeutic Intervention Translating autism spectrum disorder autosomal dominant mutation causal variant cell fate specification communication behavior comorbidity design disease phenotype disease-causing mutation experimental study functional improvement gene function genetic variant human model in vitro Model induced pluripotent stem cell insight migration mouse model mutant myelination neuron development neuropsychiatric disorder novel novel therapeutics oligodendrocyte lineage oligodendrocyte precursor postnatal precursor cell predictive signature programs relating to nervous system risk variant therapeutic target transcription factor transcriptome sequencing viral rescue

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项目摘要

ASD is a common childhood disorder, which occurs in approximately 3.4 out of every 1,000 children, and requires a lifetime of care that leads to a significant burden for both families and state agencies. Core features of ASD include deficits in socialization, communication and behavior, and can present with other comorbidities such as intellectual disability, epilepsy, anxiety, depression, attention deficits and sleep disorders. The majority of ASD cases are complex and classified as sporadic, having a multitude of factors that combine to produce a disease phenotype; however, approximately 20% of ASD cases are syndromic with a well-established genetic cause. Despite the genetic heterogeneity between different types of syndromic ASD, these disorders display an incredible amount of phenotypic overlap. This overlap may indicate that the causal mutations across disorders, funnel through common molecular pathways during neuronal development, and thus indicate the potential for generalizable treatments. Currently, pharmacotherapies are severely lacking, as no effective pharmacological agents currently exist to treat core ASD symptoms. Therefore, further research into the neurobiology and underlying pathophysiology of ASD is required. In our grant, we propose to model ASD by developing cell and animal models in which the ASD risk gene transcription factor 4 (TCF4) is mutated. TCF4 is associated with a rare neurodevelopmental model called Pitt Hopkins Syndrome (PTHS) that displays autism features. We hope by modeling this disorder we can identify cellular and molecular mechanisms associated with risk for ASD that will eventually lead to the discovery of therapeutic interventions. In Aim 1, we demonstrate that Tcf4 regulates the development of oligodendrocytes (OLs) and mutations in Tcf4 result in hypomyelination. Our preliminary data from a mutant Tcf4 mouse model suggests that Tcf4 regulates the differentiation of oligodendrocyte precursor cells (OPCs) into mature OLs and this leads to a significant decrease in myelination. We propose experiments to identify cellular and molecular mechanism for how Tcf4 regulates OPC differentiation. In Aim 2, we propose experiments to connect Tcf4-dependent hypomyelination to physiological and behavioral deficits by specifically manipulating Tcf4 expression only in the OL-lineage. Moreover, we propose to rescue physiological and behavioral deficits by postnatally reinstating Tcf4 expression only in the OL-lineage to determine if this target rescue of myelination can lead to normalization of physiological and behavioral deficits. In Aim 3, we propose to use PTHS patient-derived induce pluripotent stem cells (IPSCs) to determine if OPC differentiation phenotypes observed in our mouse models translate into human models of disease. Together, these Aims are designed to identify therapeutic targets for the treatment of PTHS and potentially other ASDs.

ASD是一种常见的儿童疾病，每1000名儿童中约有3.4次发生，需要一生的护理，这会给家庭和州机构带来巨大的负担。 ASD的核心特征包括社会化，沟通和行为的缺陷，并且可以呈现其他合并症，例如智力残疾，癫痫，焦虑，抑郁，注意力缺陷和睡眠障碍。大多数ASD病例很复杂，并被归类为零星，具有多种因素结合起来产生疾病表型的因素。但是，大约20％的ASD病例是综合症，具有良好的遗传原因。尽管不同类型的综合症ASD之间存在遗传异质性，但这些疾病表现出令人难以置信的表型重叠。这种重叠可能表明，神经元发育过程中跨疾病的因果突变，通过常见分子途径进行漏斗，从而表明了可推广治疗的潜力。目前，严重缺乏药物治疗，因为目前尚无有效的药理剂来治疗核心ASD症状。因此，需要进一步研究ASD神经生物学和潜在的病理生理学。在我们的赠款中，我们建议通过开发ASD风险基因的细胞和动物模型来建模ASD 转录因子4（TCF4）被突变。 TCF4与称为Pitt的罕见神经发育模型有关霍普金斯综合征（PTHS）显示自闭症特征。我们希望通过对这种疾病进行建模，我们可以确定与ASD风险相关的细胞和分子机制，最终会导致发现治疗干预措施。在AIM 1中，我们证明TCF4调节少突胶质细胞（OLS）的发展和突变 TCF4导致低切率。我们来自突变体TCF4小鼠模型的初步数据表明TCF4 调节少突胶质细胞前体细胞（OPC）的分化为成熟OLS，这导致了髓鞘质量显着下降。我们提出了实验，以鉴定细胞和分子机制的 TCF4如何调节OPC分化。在AIM 2中，我们提出了实验以连接TCF4依赖性的通过专门操纵TCF4表达仅在生理和行为缺陷中低切术 ol-linege。此外，我们建议通过产后恢复来挽救生理和行为缺陷仅在OL-Linege中表达TCF4，以确定此目标拯救是否会导致生理和行为缺陷的归一化。在AIM 3中，我们建议使用PTH的患者来源诱导多能干细胞（IPSC）来确定在小鼠中观察到的OPC分化表型是否模型转化为人类疾病模型。这些目标共同旨在识别治疗治疗PTH和其他ASD的靶标。