Functional Analysis of the 22q11.2 schizophrenia susceptibility genes

描述（由申请人提供）：现在很明显，许多精神和神经发育障碍以及认知功能障碍的病例是由于高度渗透性的罕见遗传变异所致。22q11.2缺失是这种变异的一个突出例子。染色体22q11.2缺失的携带者，主要是从头发生的，表现出一系列的认知缺陷，并以25- 30%的比率在青春期或成年早期发展为精神分裂症。复发性22q11.2缺失占一般人群中散发性精神分裂症病例的1-2%。由于其在精神疾病和认知功能障碍的遗传景观中的主导作用，22q1.2缺失的功能分析为开发这些疾病的新疗法提供了必要的生物学见解。在这个项目中，我们建议研究22q11.2缺失对神经元结构和功能的影响。我们提出的研究重点是使用最先进的技术，可靠的动物模型和患者来源的神经元来解决这个非常重要的问题，旨在提高我们对突变导致的事件链的理解，通过其对神经细胞和电路的影响，临床表型，并为新疗法的开发提供信息。我们努力的一个主要方面将是实施精心控制的翻译范式，以测试我们在患者神经元的小鼠模型中发现的许多改变。沿着这些路线，我们建议在人类和小鼠之间进行详细的比较研究，使用来自携带22 q11.2缺失的人类诱导多能干细胞（iPSC）的皮质神经元。这种方法的力量是不可否认的，因为它将允许在单个神经元和突触的水平上进行深入分析， 否则患者无法接触到。

DESCRIPTION (provided by applicant): It is now evident that many cases of psychiatric and neurodevelopmental disorders, as well as disorders of cognitive function, are due to highly penetrant, rare genetic variants. 22q11.2 deletion is a prominent example of such a variant. Carriers of deletions in chromosome 22q11.2, which predominantly occur de novo, exhibit a spectrum of cognitive deficits and develop schizophrenia in adolescence or early adulthood at a rate of 25-30%. Recurrent 22q11.2 deletions account for as many as 1-2% of cases of sporadic schizophrenia in the general population. Because of its leading role in the genetic landscape of psychiatric disease and cognitive dysfunction, functional analysis of the 22q1.2 deletion holds great promise for providing the biological insights necessary for development of new treatments for these conditions. In this project, we propose to study the impact of 22q11.2 deletions on neuronal structure and function in exquisite depth. Our proposed research focuses on this highly significant problem using state-of-the-art techniques, reliable animal models, and patient- derived neurons, and is designed to improve our understanding of the chain of events leading from the mutation, through its effects on neural cells and circuits, to clinical phenotype and inform the development of new therapeutics. A major aspect of our effort will be to implement carefully controlled translational paradigms to test many of the alterations that we find in mouse models in neurons from patients. Along these lines, we propose to pursue detailed comparative studies between human and mouse, using cortical neurons derived from induced pluripotent stem cells (iPSCs) from humans carrying the 22q11.2 deletion. The strength of this approach is undeniable since it will allow in-depth analysis at the level of the individual neuron and synapse, which are otherwise inaccessible in patients.