Engrafting human neurons into animal models to study schizophrenia

描述（由申请人提供）：精神分裂症影响超过1%的世界人口，包括300万美国人，是一种使人衰弱的精神障碍，其特征在于一系列症状，包括幻觉、妄想、难以表达情绪以及注意力和记忆力缺陷。尽管目前有抗精神病药物，但精神分裂症患者的预期寿命比一般人群低10年，容易滥用药物，无家可归，并有自杀的危险。因此，无论是对患有这种疾病的个人的生命还是对公共健康的影响， 成本是巨大的。目前还没有治愈精神分裂症的方法，对疾病原因的研究，包括大脑中的解剖和生理破坏，一直很困难，因为对患者细胞的潜在病理学知之甚少。 为了阐明在精神分裂症患者中发现的解剖和生理缺陷，该提议将通过将重编程的人诱导性多能干细胞（iPSC）移植到动物系统中来开发一种新的疾病模型。在该补助金的指导部分，解剖（目标1）和生理缺陷（目标2）发生在神经元来自精神分裂症患者的特点。这两个目标都在进行中，精神分裂症干细胞已经成功地植入小鼠体内。此外，已经开发了用于研究这些细胞的解剖和生理复杂性的新的计算方法。基于前两个目标中的发现，本提案的独立部分（目标3）将把个体细胞中识别的解剖学和生理学干扰与患者中被干扰的神经元活动的全局模式联系起来。 拟议的研究有可能为精神分裂症的生物学基础提供基本的见解。该项目中开发的结果和工具将推进对神经元功能的基本理解，并可能为高通量检测铺平道路，从而筛选治疗该疾病的新药物疗法。

DESCRIPTION (provided by applicant): Affecting over 1% of the world's population, including 3 million Americans, schizophrenia is a debilitating psychiatric disorder characterized by an array of symptoms including hallucinations, delusions, difficulty expressing emotions, and deficits in attention and memory. Despite the currently available antipsychotics, patients suffering schizophrenia have a life expectancy 10 years lower than that of the general population, are prone to substance abuse, homelessness, and are at risk of suicide. As a result, both the toll exacted on the lives of individuals suffering from the disorder and the public health costs are substantial. There is currently no cure for schizophrenia, and research into the causes of the disease, including the anatomical and physiological disruptions in the brain, has been difficult because little is known about the underlying pathology of cells in patients. To elucidat the anatomical and physiological deficits found in the patients with schizophrenia, this proposal will develop a novel model for the disorder by transplanting reprogrammed human inducible pluripotent stem cells (iPSCs) into an animal system. During the mentored portion of this grant, the anatomical (Aim 1) and physiological deficits (Aim 2) that occur in neurons derived from patients with schizophrenia will be characterized. Both aims are underway, and schizophrenia stem cells have been successfully engrafted into mice. Additionally, novel computational methods for studying the anatomical and physiological complexity of these cells have been developed. Based on the discoveries made in the first two aims, the independent portion of this proposal (Aim 3) will relate the anatomical and physiological disruptions identified in individual cells to the global patterns of neuronal activity that are disrupted in patients. The proposed studies have the potential to provide fundamental insights into the biological basis of schizophrenia. The results and tools developed in this project will advance the basic understanding of neuronal function, and could pave the way for high-throughput assays with which to screen new drug therapies for the treatment of the disorder.