Phenotyping Astrocytes in Human Neurodevelopmental Disorders

描述（由申请人提供）：我们建议研究星形胶质细胞成熟和功能缺陷是否有助于人类神经发育障碍（NDD）（包括自闭症和精神分裂症）的病理生理学。长期以来被认为主要是被动细胞，近年来，我们的实验室和其他人发现啮齿动物星形胶质细胞强烈刺激兴奋性和抑制性突触的形成和功能（Eroglu和Barres，2010）。类似地，当人类神经元由胚胎或诱导多能干细胞（iPSC）产生时，除非存在星形胶质细胞，否则它们很少形成突触。最近的研究表明，自闭症和精神分裂症是突触疾病。星形胶质细胞缺陷是否会导致常见的破坏性NDD的病理生理学？在本申请中，我们将利用iPSC技术研究来自自闭症和精神分裂症患者的iPSC的星形胶质细胞的发育和功能（我们的斯坦福大学同事和这些研究的合作者Ricardo Dolmetsch将提供这些iPSC）。在我们的第一个目标中，我们将表征并比较通过已建立的方法由iPSC产生的人星形胶质细胞与急性分离的人胎儿星形胶质细胞的分子表型，然后产生改进的方法以更快地从iPSC产生人星形胶质细胞，其更接近于从实际人脑组织中急性分离的胎儿星形胶质细胞的基因谱。在我们的第二个目标中，我们将表征来自NDD患者的iPSC细胞的星形胶质细胞的表型。在我们的第三个目标中，我们将确定NDD患者的星形胶质细胞是否在促进突触形成和功能方面存在缺陷。这些研究有可能为人类自闭症和精神分裂症的神经发育基础提供新的线索，有可能识别控制突触形成和功能的新型星形胶质细胞基因，并将为从iPSC生成人类星形胶质细胞产生新的方法和药物测试平台。

DESCRIPTION (provided by applicant): We propose to investigate whether defects in astrocyte maturation and function contribute to the pathophysiology of human neurodevelopmental disorders (NDD) including autism and schizophrenia. Long thought to be primarily passive cells, in recent years, our laboratory and others have found that rodent astrocytes powerfully stimulate both excitatory and inhibitory synapse formation and function (Eroglu and Barres, 2010). Similarly, when human neurons are generated from embryonic or induced pluripotent stem cells (iPSCs), they form few synapses unless astrocytes are present. An emerging theme from recent research is that autism and schizophrenia are diseases of synapses. Could astrocyte defects contribute to the pathophysiology of common devastating NDD? In this application, we will take advantage of iPSC technology to study the development and function of astrocytes derived from iPSCs from patients who have autism and schizophrenia (Ricardo Dolmetsch, our Stanford colleague and collaborator in these studies, will provide these iPSCs). In our first aim, we will characterize and compare the molecular phenotype of human astrocytes generated by iPSCs by established methods to acutely isolated human fetal astrocytes, and then generate improved methods to more quickly generate human astrocytes from iPSCs that more closely resemble the gene profiles of acutely isolated fetal astrocytes from actual human brain tissue. In our second aim, we will characterize the phenotypes of astrocytes derived from iPSC cells from patients with NDD. In our 3rd aim, we will determine whether astrocytes from NDD patients are defective in promoting synapse formation and function. These studies have the potential to shed new light on the neural developmental basis of autism and schizophrenia in humans, have the potential to identify novel astrocyte genes that control synapse formation and function, and will generate new methods and drug testing platforms for human astrocyte generation from iPSCs.