Project 44.2: Deciphering mechanisms and biomarkers of autism through mutations in the SHANK3 gene: A Translational approach

孤独症是一种广泛存在的神经发育综合征，其特征是社会互惠和沟通的缺陷，以及重复行为的存在。鉴于世界范围内自闭症的增加，迫切需要有效的干预措施。然而，这是阻碍了我们的理解的causal机制，主要是由于自闭症的病因学的异质性。在这方面，单基因形式的自闭症，如由SHANK 3基因突变引起的麦克德米德综合征（PMS），更适合于阐明自闭症的病理生理学。在我们的转化研究中，人类和啮齿动物的研究结合在一起，以阐明自闭症的神经生物学基础。我们提供博士机会加入我们的团队，与人类和啮齿动物一起研究与SHANK 3基因突变相关的生物学。我们使用MRI作为一种翻译工具来检查大脑的结构，功能和生物化学。我们的目标是在我们的患者群体中定义与PMS/自闭症有关的大脑系统，然后确定这些特征是否可以在携带相同突变的啮齿动物中重现。这种反向翻译到动物模型中，再加上尖端的方法（例如透明脑中的3D成像（PERIITY），光遗传学，电生理学），将使我们能够确认脑缺陷的细胞基础并产生新的治疗靶点。在第一年，学生将学习技术技能，并开始获取MRI数据。在第二年和第三年，他们将更详细地研究SHANK 3突变的神经生物学。这个多学科的项目提供了一系列杰出的技能，并有可能迅速影响我们对自闭症的理解。

Autism is a pervasive neurodevelopmental syndrome characterized by deficits in social reciprocity andcommunication, and presence of repetitive behaviours. Given the worldwide increase in autism, effectiveinterventions are urgently needed. This is however hampered by our poor understanding of causalmechanisms, mainly due to autism's heterogeneity in aetiology. In that respect, single-gene forms ofautism, such as the Phelan McDermid Syndrome (PMS) caused by a mutation in the SHANK3 gene, arebetter suited to elucidate the pathophysiology of autism.In our translational research, human and rodent studies are combined to elucidate the neurobiologicalunderpinnings of autism. We offer a PhD opportunity to join our team and work with humans and rodentsto examine the biology associated with SHANK3 gene mutations. We use MRI as a translational tool toexamine the brain structure, function and biochemistry. We aim to define the brain systems involved inPMS/autism in our patient populations and then establish whether these signatures can be recapitulatedin rodents carrying the same mutation. This back-translation into animal models coupled with cutting-edge methods (e.g. 3D imaging in transparent brains (CLARITY), optogenetics, electrophysiology) willallow us to confirm the cellular basis of brain deficits and generate novel treatment targets. In the firstyear the student will learn technical skills and begin to acquire MRI data. In the second and third years,they will examine in more detail the neurobiology of SHANK3 mutation. This multidisciplinary projectprovides an outstanding array of skills and a potential to rapidly impact upon our understanding of autism.