Do Astrocytes Cause Neurodevelopmental Disorders?

描述（由申请人提供）：长期以来，星形胶质细胞主要被认为是被动细胞，在发育过程中，星形胶质细胞在刺激新突触的形成和功能以形成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，并提出了一个问题，即星形胶质细胞的功能缺陷是否会导致常见的破坏性神经发育障碍的病理生理学。在这里，我建议使用新技术来急性纯化人类原代星形胶质细胞，以及从悬浮神经球中产生诱导多能干细胞（iPSC）衍生的星形胶质细胞的方案。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。为了证明这个新模型系统的可行性，我将专注于从22q11缺失综合征患者产生的iPSCs中生成星形胶质细胞。这些人患有神经发育迟缓，是患精神分裂症的遗传风险最高的人群。在22q11染色体缺失的候选基因中，星形胶质细胞富集酶脯氨酸脱氢酶（PRODH）在小鼠神经功能障碍的敲除研究中已经被证明是一个有希望的参与者。我的工作是从22q11患者中产生ipsc衍生的星形胶质细胞，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22q11例患者中发现的结果外，本提案中开发的技术为研究星形胶质细胞在许多神经发育和神经精神疾病中的作用提供了机会。

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.