Modelling psychosis using DISC1 human induced pluripotent stem cells

精神分裂症和主要精神疾病是非常常见的疾病，其病因尚不完全清楚，我们的治疗也只是部分有效。已知它们是高度家族性的（遗传的），一些遗传风险因素，包括影响DISC位点的因素，足以在很大比例的携带它们的个体中引起这些疾病。众所周知，大脑结构和功能的异常与这些遗传因素密切相关。然而，这些异常和临床疾病背后的细胞机制仍不清楚，主要是因为人脑在体内无法进入。然而，最近有可能通过对皮肤成纤维细胞进行重编程，使其成为神经元和其他神经细胞类型，从而在体外研究脑细胞。我们建议研究来自有或没有致病易位的个体的体外神经组织。首先，我们将对其成纤维细胞进行重编程，使其成为多能干细胞、神经祖细胞和神经元，然后对其进行广泛的验证和表征。然后，我们将通过一系列神经祖细胞增殖、神经元形态学和生理学的比较研究，以及随后特别关注影响DISC1/2和谷氨酸（NMDA）受体表达的过程，来研究疾病风险如何在细胞水平上被授予。

Schizophrenia and major mental illness are very common conditions whose aetiology is imperfectly understood and for which our treatments are only partially effective. They are known to be highly familial (genetic) and some genetic risk factors, including those affecteing the DISC locus, are sufficient to cause these disorders in a large proportion of individuals who carry them. It is also known that abnormalities of brain structure and function are closely linked to these genetic factors. The cellular mechanisms underlying these abnormalities and clinical disorder are however still unclear, largely becuase the human brain is inaccessable in vivo. However, it has recently become possible to study brain cells in vitro by reprogramming skin fibroblasts to become neurones and other neural cell types. We propose to study in vitro neural tissue derived from individuals with and without disease-causing translocation at the DISC locus. First, we will reprogramme their fibroblasts to become pluripotent stem cells, neural progenitors and neurons which will then be extensively validated and characterised. We will then examine how disease risk is conferred at a cellular level through a series of comparative studies of neural progenitor proliferation, neuronal morphology and physiology, and later by focussing specifically on the processes affected DISC1/2 and glutamate (NMDA) receptor expression.