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

自闭症是一种普遍存在的神经发育综合症，其特征是缺乏社会互惠和沟通，并存在重复行为。鉴于自闭症在全球范围内的增加，迫切需要有效的干预措施。然而，这是因为我们对自闭症的致病机制缺乏了解，这主要是由于自闭症在病因学上的异质性。在这方面，单基因形式的自闭症，如由SHANK3基因突变引起的费兰-麦克德米德综合征(PMS)，更适合于阐明自闭症的病理生理学。在我们的翻译研究中，结合人类和啮齿动物的研究来阐明自闭症的神经生物学基础。我们提供一个博士机会加入我们的团队，与人类和机器人合作，研究与SHANK3基因突变相关的生物学。我们使用核磁共振作为一种翻译工具来检查大脑的结构、功能和生化。我们的目标是在我们的患者群体中定义涉及经前综合症/自闭症的大脑系统，然后确定这些特征是否可以在携带相同突变的啮齿动物身上重现。这种反向转化为动物模型的方法与尖端方法(例如，透明大脑的3D成像(Clarity)、光遗传学、电生理学)将使我们能够确认大脑缺陷的细胞基础，并产生新的治疗靶点。在第一年，学生将学习技术技能，并开始获取核磁共振数据。在第二年和第三年，他们将更详细地研究SHANK3突变的神经生物学。这个多学科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.