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都是由于高渗透性、罕见的基因变异所致。22q11.2缺失就是这种变体的一个突出例子。染色体22q11.2缺失的携带者主要发生在新生，表现出一系列认知缺陷，并在青春期或成年早期以25%-30%的比例发展成精神分裂症。在普通人群中，反复发生的22q11.2缺失占散发性精神分裂症病例的1-2%。由于22q1.2缺失在精神疾病和认知功能障碍的遗传图景中的主导作用，22q1.2缺失的功能分析为这些疾病的新治疗方法的开发提供了必要的生物学见解。在这个项目中，我们打算在精细的深度研究22q11.2缺失对神经元结构和功能的影响。我们提议的研究集中在这个非常重要的问题上，使用最先进的技术、可靠的动物模型和患者来源的神经元，旨在提高我们对从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，到临床表型，并为新疗法的发展提供信息。我们努力的一个主要方面将是实施仔细控制的翻译范例，以测试我们在患者神经元的小鼠模型中发现的许多变化。沿着这些思路，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22q11.2缺失的人类诱导多能干细胞(IPSCs)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水平上进行深入分析， 否则患者无法接触到这些信息。

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.