Phenotyping Astrocytes in Human Neurodevelopmental Disorders

描述(申请人提供)：我们建议调查星形胶质细胞成熟和功能缺陷是否与包括自闭症和精神分裂症在内的人类神经发育障碍(NDD)的病理生理学有关。长期以来，我们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能够有力地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的多能干细胞(IPSCs)产生时，它们形成的突触很少，除非存在星形胶质细胞。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。星形胶质细胞缺陷是否与常见的破坏性新城疫的病理生理学有关？在这项应用中，我们将利用IPSC技术来研究来自自闭症和精神分裂症患者的IPSCs来源的星形胶质细胞的发育和功能(我们的斯坦福大学同事、这些研究的合作者Ricardo Dolmetsch将提供这些IPSCs)。在我们的第一个目标中，我们将通过已建立的急性分离人胎儿星形胶质细胞的方法来表征和比较IPSCs产生的人星形胶质细胞的分子表型，然后产生更快地从IPSCs产生人星形胶质细胞的改进方法，该方法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图谱。在我们的第二个目标中，我们将表征来自NDD患者的IPSC细胞来源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在促进突触形成和功能方面是否存在缺陷。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，有可能发现控制突触形成和功能的新的星形胶质细胞基因，并将为从IPSCs产生人类星形胶质细胞创造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.