Regulation of neuronal survival by gamma protocadherins

描述（由申请人提供）：神经元死亡不仅对于塑造发育中的神经系统的大小和连接性至关重要，而且对神经退行性疾病和中风的发病机制也有显着贡献。 越来越多的遗传证据表明，簇状原钙粘蛋白（Pcdhs）在神经元存活的调节中发挥着重要作用。我们的初步数据表明，PDCD10（也称为 CCM3）是人类脑海绵状血管瘤的一种致病基因缺陷，作用于 Pcdh-α 的下游来介导此功能。为了更好地了解 Pcdhs 调节神经元存活的分子途径，我们将通过使用转基因小鼠模型评估 PDCD10 蛋白质相互作用网络中各个成分的作用来定义 PDCD10 下游的分子途径。 公共健康相关性：发育性神经元死亡可确保神经系统的适当大小和连接性，成年期的异常神经元死亡通常与慢性神经退行性疾病（如阿尔茨海默病）和急性脑缺血/中风有关。 该项目的目的是阐明神经元如何通过细胞表面分子原钙粘蛋白大家族发出信号来调节正常发育过程中的神经元存活，以及该通路的错误调节如何导致神经变性。

DESCRIPTION (provided by applicant): Neuronal death is not only essential in shaping the size and connectivity of the developing nervous system, but also contributes significantly to the pathogenesis of neurodegenerative diseases and stroke. Accumulating genetic evidence shows that clustered protocadherins (Pcdhs) play an important role in the regulation of neuronal survival. Our preliminary data show that PDCD10, also known as CCM3, a causative genetic defect for Cerebral Cavernous Malformations in human, acts downstream of Pcdh-?s to mediate this function. To better understand molecular pathways by which Pcdhs regulate neuronal survival, we will define the molecular pathways downstream of PDCD10 by evaluating the role of individual components in PDCD10 protein interaction network using genetically modified mouse models. PUBLIC HEALTH RELEVANCE: Developmental neuronal death ensures the appropriate size and connectivity of the nervous system and aberrant neuronal death in adulthood is commonly associated with chronic neurodegenerative diseases such as Alzheimer's disease, and acute cerebral ischaemia/stroke. The objective of this project is to elucidate how neurons signal through a large family of cell surface molecules-protocadherins to regulate neuronal survival during normal development and how misregulation of this pathway leads to neurodegeneration.