Role of PCDH12 in neural circuit formation during brain development and disease

 描述（由申请人提供）：人脑包含数十亿个轴突，这些轴突遵循建立功能连接所必需的精确路径。尽管进行了大量的努力，但只有少数由轴突引导错误引起的疾病被鉴定出来，其中它们的分子病因尚未阐明。我已经确定了PCDH 12在大脑连接异常的家庭中的突变。我现在计划扩大筛选范围，以确定与大脑布线缺陷相关的其他新基因突变。确定遗传原因不仅将阐明病理机制，而且还将提供有关发育过程中细胞和分子机制的见解。迄今为止，了解神经发育障碍的一个主要挑战是缺乏受影响的组织。从患者诱导的多能干细胞（iPSC）分化神经组织的能力为揭示疾病的独特人类特征开辟了一条令人兴奋的途径。因此，在该奖项的指导阶段，我建议利用iPSC和动物模型的组合来揭示在没有PCDH 12的情况下轴突引导和神经回路形成的分子基础。在独立阶段，I将进行机制研究，以表征PCDH 12和Cofilin之间的功能相互作用，这些相互作用与iPSC和小鼠疾病模型中的轴突指导有关，利用在该奖项的指导阶段获得的技能。为了进行这项研究，我从患者和对照成纤维细胞中产生了iPSC，并开始对Pcdh 12-/-小鼠进行表征。我的长期目标是将我在神经元死亡和突触形成方面的背景与轴突引导方面的专业知识相结合;这将在拟议的培训中获得，以便更好地了解大脑布线缺陷。我的目标是整合人类遗传学，动物和干细胞疾病模型，以阐明有关神经回路形成的分子机制。我相信，这种技术的结合将提供对人类大脑如何发育的见解，并彻底改变我们对神经发育障碍的理解，为开发新疗法奠定基础。

 DESCRIPTION (provided by applicant): The human brain contains billions of axons that follow precise pathways essential for the establishment of functional connections. Despite intensive efforts, only few disorders resulting from errors in axon guidance have been identified wherein, their molecular etiologies have not been elucidated. I have identified mutations in PCDH12 in families presenting abnormalities in brain connectivity. I now plan to broaden the screening to identify additional novel gene mutations related to brain wiring defects. Identifying genetic causes will not only shed light on the pathological mechanisms but also will provide insight about the cellular and molecular machinery during development. A major challenge for understanding neurodevelopmental disorders to date, has been the lack of affected tissue. The capacity to differentiate neural tissue from patient induced pluripotent stem cells (iPSCs) opens an exciting avenue to reveal unique human features of disease. Thus, during the mentored phase of this award, I propose to utilize a combination of iPSC and animal models to uncover the molecular basis underlying axon guidance and neural circuit formation in the absence of PCDH12. During the independent phase I will conduct mechanistic studies to characterize the functional interaction between PCDH12 and Cofilin pertaining to axon guidance in both iPSC and mouse disease models, utilizing the skills obtained during the mentored phase of the award. To pursue the proposed research, I have generated iPSCs from patient and control fibroblasts and I have started the characterization of Pcdh12-/- mice. My long-term goal is to combine my background in neuronal death and synapse formation with the expertise in axon guidance; which will be acquired during the proposed training, in order to better understand brain wiring defects. I aim to integrate human genetics, animal, and stem cell disease models to elucidate the molecular mechanisms pertaining to neural circuit formation. I believe that this combination of techniques will provide insights into how the human brain develops and revolutionize our understanding of neurodevelopmental disorders, laying the groundwork for developing new therapies.