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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：
10636832
负责人：
BRADY J MAHER
金额：
$ 62.76万
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/10636832
关键词：
Adult Animal Model Anxiety Attentional deficit Award Behavior Behavioral Biological Assay Biological Models Biological Process Biology Brain Caring Cell Differentiation process Cell model Cells Cellular biology Central Nervous System ChIP-seq Child Childhood Chronic Classification Clinical Communication Complex Data Development Developmental Process Diagnosis Disease Disease model Electrophysiology (science)Epilepsy Etiology Family Functional disorder Gene Expression Profile Genes Genetic Genetic Heterogeneity Genetic Transcription 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 Neurobiology Neurons Oligodendroglia Outcome PF4 Gene Pathway interactions Patients Pharmacotherapy Phenotype Physiological Physiology Pitt-Hopkins syndrome Psychiatry Public Health Regulation Research Risk Role Sleep Disorders Socialization Symptoms Therapeutic Intervention Translating autism spectrum disorder autosomal dominant mutation causal variant cell fate specification comorbidity design disease phenotype disease-causing mutation experimental study functional improvement gene function genetic variant human model improved in vitro Model induced pluripotent stem cell insight migration mouse model mutant myelination neural neuron development neuropsychiatric disorder novel novel therapeutics oligodendrocyte lineage oligodendrocyte precursor pharmacologic postnatal precursor cell predictive signature programs risk variant therapeutic target transcription factor transcriptome sequencing viral rescue

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.

自闭症是一种常见的儿童疾病，每1000名儿童中约有3.4人患有自闭症，需要终生护理，这给家庭和国家机构带来了沉重的负担。ASD的核心特征包括社交、沟通和行为方面的缺陷，并可出现其他共病，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病例是复杂的和散发性的，有多种因素结合在一起产生疾病表型；然而，大约20%的ASD病例是具有明确遗传原因的综合征。尽管不同类型的综合征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，在神经元发育过程中，因果突变跨障碍、漏斗通过常见的分子途径，从而表明可推广治疗的可能性。目前，药物治疗严重缺乏，因为目前还没有有效的药理学药物来治疗ASD的核心症状。因此，需要对ASD的神经生物学和潜在的病理生理学进行进一步的研究。在我们的资助中，我们建议通过发展ASD风险基因的细胞和动物模型来建立ASD模型转录因子4(TCF4)发生突变。TCF4与一种罕见的神经发育模型PITT有关表现出自闭症特征的霍普金斯综合征(PTHS)。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将导致发现治疗性干预。在目标1中，我们证明了TCF4调节少突胶质细胞(OL)的发育和在 TCF4可导致髓鞘过少。我们来自突变的TCF4小鼠模型的初步数据表明，TCF4 调节少突胶质前体细胞(OPC)向成熟OL的分化，从而导致髓鞘形成显著减少。我们建议进行实验，以确定细胞和分子机制 TCF4如何调控OPC分化。在目标2中，我们提出了连接依赖TCF4的实验特异地调控TCF4表达的下髓鞘对生理和行为缺陷的影响 OL血统。此外，我们建议通过生后恢复来挽救生理和行为缺陷 TCF4仅在OL谱系中表达，以确定这种靶向挽救髓鞘是否可以导致生理和行为缺陷的正常化。在目标3中，我们建议使用PTHS患者来源的诱导多能干细胞(IPSCs)以确定在我们的小鼠中观察到的OPC分化表型模型转化为人类的疾病模型。总而言之，这些目标旨在确定治疗方法 PTHS和潜在的其他ASD的治疗目标。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner.

DOI：
10.1038/mp.2017.37
发表时间：
2018-03
期刊：
Molecular psychiatry
影响因子：
11
作者：
Page SC;Hamersky GR;Gallo RA;Rannals MD;Calcaterra NE;Campbell MN;Mayfield B;Briley A;Phan BN;Jaffe AE;Maher BJ
通讯作者：
Maher BJ

CaPTure: Calcium PeakToolbox for analysis of in vitro calcium imaging data.

DOI：
10.1186/s12868-022-00751-7
发表时间：
2022-11-30
期刊：
BMC NEUROSCIENCE
影响因子：
2.4
作者：
Tippani, Madhavi;Pattie, Elizabeth A.;Davis, Brittany A.;Nguyen, Claudia V.;Wang, Yanhong;Sripathy, Srinidhi Rao;Maher, Brady J.;Martinowich, Keri;Jaffe, Andrew E.;Page, Stephanie Cerceo
通讯作者：
Page, Stephanie Cerceo

Using Induced Pluripotent Stem Cells to Investigate Complex Genetic Psychiatric Disorders.