Regulation of neuronal survival by gamma protocadherins

描述（由申请人提供）：神经元死亡不仅在形成发育中的神经系统的大小和连接性方面至关重要，而且在神经退行性疾病和中风的发病机制中也有重要作用。 越来越多的遗传学证据表明，成簇原钙粘素（Pcdhs）在神经元存活的调节中起着重要作用。我们的初步数据表明，PDCD 10，也被称为CCM 3，一个致病的遗传缺陷，脑海绵状血管畸形在人类，行为下游的Pcdh-？s来调节此功能。为了更好地了解Pcdhs调节神经元存活的分子途径，我们将通过使用遗传修饰的小鼠模型评估PDCD 10蛋白相互作用网络中单个组分的作用来定义PDCD 10下游的分子途径。 公共卫生相关性：发育性神经元死亡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/中风相关。 本项目的目的是阐明神经元如何通过一个大家族的细胞表面分子-原钙粘蛋白来调节正常发育过程中神经元的存活，以及该通路的失调如何导致神经退行性变。

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.