Regulation of neuronal survival by gamma protocadherins

γ 原钙粘蛋白对神经元存活的调节

• 批准号: 8445778
• 负责人: XIAOZHONG ALEC WANG
• 金额: $ 23.18万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445778
• 关键词: Acute; Adaptor Signaling Protein; Adult; Affect; Alleles; Alzheimer' s Disease; Apoptosis; Apoptotic; Attenuated; Binding; Cavernous Malformation; Cell surface; Cells; Cerebral Ischemia; Cerebrum; Cessation of life; Chickens; Chronic; Cytoplasmic Tail; Data; Development; Dominant-Negative Mutation; Ectopic Expression; Ensure; Experimental Models; Family; Genetic; Human; In Vitro; Individual; Interneurons; Investigation; Knockout Mice; MAP Kinase Gene; MAPK14 gene; Mediating; Membrane; Mitochondria; Modeling; Molecular; Mus; Mutation; Nature; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway interactions; Phosphorylation; Play; Population; Process; Protein Isoforms; Proteins; Reactive Oxygen Species; Regulation; Retinal Ganglion Cells; Role; Shapes; Signal Pathway; Signal Transduction; Spinal; Spinal Cord; Stroke; Synapses; Testing; Work; attenuation; excitotoxicity; in vivo; in vivo Model; mouse model; nervous system development; neurodevelopment; neuron apoptosis; neuronal cell body; neuronal survival; neurotrophic factor; postsynaptic; presynaptic; protein aggregate; protein complex; protein protein interaction; research study; spinal pathway

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.

描述(由申请人提供)：神经元死亡不仅对形成发育中的神经系统的大小和连通性至关重要，而且对神经退行性疾病和中风的发病机制也有重要影响。越来越多的遗传学证据表明，聚集型原钙粘附素(Pcdhs)在神经元存活的调控中发挥着重要作用。我们的初步数据表明，PDCD10，也被称为CCM3，是人类脑海绵状血管畸形的致病基因缺陷，在PcdH-？S的下游起调节作用。为了更好地了解Pcdhs调控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蛋白相互作用网络中单个成分的作用来定义PDCD10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，成年后神经元异常死亡通常与阿尔茨海默病和急性脑缺血/中风等慢性神经退行性疾病有关。本项目的目的是阐明神经元如何通过一大类细胞表面分子--原钙粘附素来调节神经元在正常发育过程中的存活，以及这一途径的错误调控如何导致神经退行性变。