The PAR-6/aPKC Polarity Complex in Synaptic Assembly and Function

突触组装和功能中的 PAR-6/aPKC 极性复合体

• 批准号: 8414161
• 负责人: Huaye Zhang
• 金额: $ 7.91万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414161
• 关键词: Actins; Address; Affect; Alzheimer' s Disease; Axon; Behavioral; Brain; Cell division; Cell surface; Cells; Clinical; Complex; Data; Dendritic Spines; Endocytosis; Environment; Epithelial; Excitatory Synapse; Glutamate Receptor; Glutamates; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Instruction; Knockout Mice; Maintenance; Mediating; Memory; Memory impairment; Mental Retardation; Mentors; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Nervous System Physiology; Neurodegenerative Disorders; Neurons; PARD6A gene; Pathway interactions; Phase; Phosphorylation; Poly(ADP-ribose) Polymerases; Process; Proteins; Recycling; Regulation; Research Proposals; Role; Schizophrenia; Signal Pathway; Signal Transduction; Structure; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Translating; Vertebral column; Vesicle; base; brain cell; cognitive function; in vivo; migration; nervous system disorder; novel; response; synaptic function; transmission process

The proposal is based on the finding that the PAR-6/aPKC complex regulates dendritic spine morphogenesis, and it does so through a novel signaling pathway involving pi90 RhoGAP and the RhoA GTPase. Studies during the mentored phase of this project revealed the small GTPase Rnd1 as a candidate protein for mediating the effects of PAR-6/aPKC on p190RhoGAP and RhoA. Aim 1 of this proposal seeks to elucidate the molecular mechanism by which the PAR-6/aPKC complex regulates Rndl. Specifically, the effect of the PAR complex on Rndl expression and phosphorylation, and Rnd/190 interaction will be examined. To further examine the role of the PAR complex in synaptic function, we will elucidate the mechanisms by which the PAR complex regulates glutamatergic synaptic transmissioin, and identify the upstream regulators of the PAR complex. Finally, we are generating PAR-6C conditional knockout mice to test the hypothesis that the PAR complex is involved in synaptic plasticity and memory formation in vivo. My long term goal is to understand the complex signaling mechanisms regulating dendritic spine morphogenesis and synaptic plasticity, and how they translate to memory formation and maintenance in vivo.

该提案基于以下发现：PAR-6/APKC复合物调节树突状脊柱 形态发生，它通过涉及PI90 Rhogap和Rhoa的新型信号通路来做到这一点 GTPase。该项目的指导阶段的研究揭示了小的GTPase RND1作为候选人 蛋白质用于介导Par-6/apkc对P190RHOGAP和RHOA的影响。本提案寻求的目标1 阐明PAR-6/APKC复合物调节RNDL的分子机制。具体来说， PAR复合物对RNDL表达和磷酸化的影响，RND/190相互作用将是 检查。为了进一步研究PAR复合物在突触功能中的作用，我们将阐明 PAR复合物调节谷氨酸能突触透射蛋白的机制，并鉴定 PAR复合体的上游调节器。最后，我们正在生成par-6c有条件的敲除小鼠 检验了PAR复合物与体内突触可塑性和记忆形成有关的假设。我的 长期目标是了解调节树突形态发生的复杂信号传导机制 和突触可塑性，以及它们如何转化为体内记忆形成和维护。