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

 描述(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，但只有少数几种疾病是由轴突引导错误引起的，其中，其分子病因尚未阐明。我已经在表现出大脑连接异常的家庭中发现了PCDH12的突变。我现在计划扩大筛查范围，以确定与大脑连接缺陷有关的其他新基因突变。确定遗传原因不仅有助于阐明发病机制，还将有助于深入了解发育过程中的细胞和分子机制。到目前为止，理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(IPSCs)中分化出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PCDH12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，我将利用在授奖指导阶段获得的技能，进行机制研究，以表征PCDH12和cofilin之间与IPSC和小鼠疾病模型中轴突指导有关的功能相互作用。为了继续这项拟议的研究，我从患者和对照成纤维细胞中培养出了IPSCs，并开始对Pcdh12-/-小鼠进行鉴定。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指导方面的专业知识结合起来；这些专业知识将在拟议的培训中获得，以便更好地了解大脑连接缺陷。我的目标是整合人类遗传学、动物和干细胞疾病模型，以阐明与神经回路形成有关的分子机制。我相信，这种技术的结合将为人类大脑如何发育提供洞察力，并彻底改变我们对神经发育障碍的理解，为开发新的治疗方法奠定基础。

 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.