Do Astrocytes Cause Neurodevelopmental Disorders?

描述(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，在发育过程中，它在刺激新突触的形成和功能以塑造神经回路方面发挥着积极的作用。最近的研究提出了一个新的主题，即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，我建议除了从悬浮神经球中产生诱导多能干细胞(IPSC)来源的星形胶质细胞的方案外，还可以使用新的技术来尖锐地纯化原代人类星形胶质细胞。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。为了证明这一新模型系统的可行性，我将重点研究22q11缺失综合征患者产生的IPSCs生成星形胶质细胞。这些人患有神经发育迟缓，是患精神分裂症的最高遗传风险之一。在22q11染色体缺失的候选基因中，从小鼠的基因敲除研究中已经证明，星形胶质细胞富集酶Pro脱氢酶(PROH)在神经功能障碍中具有很好的作用。我从22q11患者中生产IPSC来源的星形胶质细胞的工作将询问患者来源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/或突触功能缺陷。除了在22q11患者群中的发现之外，这项提案中开发的技术还提供了研究星形胶质细胞在许多神经发育和神经精神障碍中的作用的机会。

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.