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Do Astrocytes Cause Neurodevelopmental Disorders?

星形胶质细胞会导致神经发育障碍吗？

基本信息

批准号：
8936909
负责人：
Steven A Sloan
金额：
$ 3.53万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2017-09-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8936909
关键词：
22q11 22q11 Deletion Syndrome Acute Address Astrocytes Autistic Disorder Axon Biological Assay Biological Models Brain Brain region Candidate Disease Gene Cells Chromosome Deletion Coculture Techniques Collaborations Data Defect Development DiGeorge Syndrome Disease Disease Progression Enzymes Epitopes Exhibits Family Frontotemporal Dementia Functional disorder Future Gene Expression Profile Genes Genetic Risk Goals Health Human In Vitro Incidence Individual Knock-out Maintenance Mediating Methods Modeling Molecular Molecular Profiling Mus Mutation Neurodevelopmental Disorder Neurologic Dysfunctions Neurons Operative Surgical Procedures Pathology Patients Phenotype Physiological Play Primary Cell Cultures Process Proline Dehydrogenase Protocols documentation Psychiatry Research Risk Rodent Role Sampling Schizophrenia Series Serum Shapes Source Stem cells Surface Synapses Techniques Testing Tissue Sample Tissues Universities Work aging brain astrogliosis axon growth behavioral study cell behavior cell type design fetal human RNA sequencing human data in vivo induced pluripotent stem cell neglect nervous system development nervous system disorder neural circuit neurodevelopment neuron loss neuronal survival neuropsychiatry novel public health relevance research study stem cell technology synaptic function synaptogenesis transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Long considered primarily passive cells, astrocytes play an active role in stimulating the formation and function of new synapses to shape neural circuits during development. An emerging theme from recent research is that autism and schizophrenia are diseases of synapses, and raises the question whether functional defects in astrocytes could contribute to the pathophysiology of common devastating neurodevelopmental disorders. Here I propose the use of novel techniques for acutely purifying primary human astrocytes in addition to a protocol for generating induced pluripotent stem cell (iPSC) derived astrocytes from suspended neurospheres. The goal of these approaches is to address how astrocyte dysfunction might underlie neurodevelopmental disease. In order to demonstrate the feasibility of this new model system, I will focus on generating astrocytes from iPSCs produced from patients with 22q11 Deletion Syndrome. These individuals suffer from neurodevelopmental delay and are among the highest genetic risks of developing schizophrenia. Among the candidate genes in the chromosomal deletion for 22q11, the astrocyte-enriched enzyme proline dehydrogenase (PRODH) has already proven to be a promising player in neurological dysfunction from knockout studies in mice. My work to produce iPSC-derived astrocytes from 22q11 patients will ask whether patient-derived astrocytes contribute to defects in neuronal health, synaptic formation, and / or synaptic function through either cell autonomous or non-cell autonomous mechanisms. In addition to the findings within 22q11 patient lines, the techniques developed in this proposal offer the opportunity to investigate the role of astrocytes in numerous neurodevelopmental and neuropsychiatric disorders.

描述（由申请人提供）：长期以来，星形胶质细胞被认为主要是被动细胞，在刺激新突触的形成和功能以在发育期间塑造神经回路方面发挥积极作用。最近研究的一个新主题是自闭症和精神分裂症是突触疾病，并提出了星形胶质细胞功能缺陷是否可能导致常见的破坏性神经发育障碍的病理生理学的问题。在这里，我建议使用新的技术，急性纯化初级人类星形胶质细胞，除了产生诱导多能干细胞（iPSC）衍生的星形胶质细胞悬浮神经球的协议。这些方法的目标是解决星形胶质细胞功能障碍可能是神经发育疾病的基础。为了证明这种新模型系统的可行性，我将专注于从22 q11缺失综合征患者产生的iPSC中产生星形胶质细胞。这些人患有神经发育迟缓，是患精神分裂症的最高遗传风险之一。在22 q11染色体缺失的候选基因中，富含星形胶质细胞的酶脯氨酸脱氢酶（PRODH）已经被证明是小鼠敲除研究中神经功能障碍的有希望的参与者。我从22 q11患者中产生iPSC衍生的星形胶质细胞的工作将询问患者衍生的星形胶质细胞是否通过细胞自主或非细胞自主机制导致神经元健康，突触形成和/或突触功能的缺陷。除了在22 q11患者线内的发现，本提案中开发的技术提供了调查星形胶质细胞在许多神经发育和神经精神疾病中的作用的机会。