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

PCDH12 在大脑发育和疾病过程中神经回路形成中的作用

• 批准号: 8930215
• 负责人: ALICIA DIONE GUEMEZ GAMBOA
• 金额: $ 9.67万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930215
• 关键词: Actin-Binding Protein; Affect; Animal Model; Animals; Autistic Disorder; Award; Axon; Biological; Brain; Cellular biology; Cessation of life; Complex; Corticospinal Tracts; Defect; Detection; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease model; Dysplasia; Etiology; Family; Fibroblasts; Functional disorder; Gene Mutation; Genes; Genetic; Goals; Health; Human; Human Genetics; Image; Individual; Inherited; K-Series Research Career Programs; Knockout Mice; Knowledge; Lead; Light; Mediating; Mentors; Modeling; Molecular; Mus; Mutation; Natural regeneration; Nervous system structure; Neurodevelopmental Disorder; Neurons; Outcome; Pathway interactions; Patients; Pattern; Phase; Phenotype; Process; Research; Role; Schizophrenia; Stem cells; Syndrome; System; Techniques; Tissues; Training; axon growth; axon guidance; axon regeneration; base; cofilin; exome sequencing; gene discovery; human disease; induced pluripotent stem cell; insight; loss of function mutation; nervous system disorder; neural circuit; novel; relating to nervous system; screening; skills; success; synaptogenesis

 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.

 描述（由申请人提供）：人类大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，尽管付出了巨大的努力，但仅发现了少数由轴突引导错误引起的疾病，其分子病因尚未阐明。我已经在出现大脑连接异常的家族中发现了 PCDH12 突变，现在我计划扩大筛查范围，以识别与大脑线路缺陷相关的其他新基因突变。识别遗传原因不仅可以揭示病理机制。迄今为止，理解神经发育障碍的一个主要挑战是缺乏将神经组织与患者诱导的多能干细胞（iPSC）区分开来的能力。因此，在该奖项的指导阶段，我建议结合 iPSC 和动物模型来揭示在缺乏 PCDH12 的情况下轴突引导和神经回路形成的分子基础。独立相我将利用在该奖项的导师阶段获得的技能，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引导相关的功能相互作用。患者和对照成纤维细胞，我已经开始对 Pcdh12-/- 小鼠进行表征。我的长期目标是了解我的神经死亡背景，并将形成与轴突引导的专业知识相结合；在拟议的培训中，为了更好地了解大脑接线缺陷，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我们提供深入的见解。人类大脑如何发育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。