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Cytohesins, ARF GTP'ases and Neurodegeneration

细胞粘附素、ARF GTP 酶和神经变性

基本信息

批准号：
9275554
负责人：
Robert G Kalb
金额：
$ 12.6万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275554
关键词：
Ablation Actins Adaptor Signaling Protein Adult Amyotrophic Lateral Sclerosis Biological Biological Assay Biological Process Cell Adhesion Cells Cessation of life Defect Degradation Pathway Dimensions Disease Elements Equilibrium Family Frontotemporal Dementia Functional disorder Genes Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Impairment In Vitro Individual Integrins Intracellular Membranes Lead Lipids Mammals Membrane Protein Traffic Modeling Molecular Monitor Motor Motor Neurons Movement Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Pathway interactions Pharmacology Phenotype Phylogenetic Analysis Process Production Protein Family Proteins Proteome Publications Publishing RNA Interference RNA Processing Recycling Shapes Signal Transduction Sister Specificity Stress System Thinking Toxic Actions Toxic effect Ubiquitin Work base endoplasmic reticulum stress excitotoxicity experimental study in vivo Model insight interest knock-down lipid metabolism migration misfolded protein mitochondrial dysfunction mutant neuroinflammation novel therapeutics protein aggregate protein degradation protein misfolding proteostasis screening superoxide dismutase 1 therapeutic target tool trafficking

项目摘要

Abstract In vitro and in vivo models of neurodegenerative disease such as Amyotrophic Lateral Sclerosis (ALS) have provided glimpses into the biological processes that go awry in these disorders. Current thinking indicates that major pathophysiologic processes include protein misfolding and accumulation, endoplasmic reticulum stress, dysfunctional intracellular trafficking, excitotoxicity, mitochondrial dysfunction, neuroinflammation, and abnormal RNA processing. The ARF family of GTP'ases are a phylogenetically- conserved family of proteins involved with membrane traffic, lipid metabolism/signaling, actin remodeling, and lipid droplet formation. Based on the apparent overlap between ALS pathophysiology and some of the biological actions of ARFs, we wondered if ARF signaling modified models of ALS. In recently published work we find that blocking activity of cytohesins (“Cy's”, ARF guanine nucleotide exchange factors) is neuroprotective. Understanding the cell biological mechanism of this observation is problematic because of the pleiotropic actions of Cy's and ARFs. The path forward will be facilitated by determining the specific Cy and specific ARF involved in this process as this will guide us to the relevant cell biological process. To this end, in specific aim #1, experiments will be undertaken to determine if inhibition of an individual Cy confers protection against the toxic actions on motor neurons of mutant SOD or mutant TDP43. In specific aim #2, experiments will be undertaken to determine if inhibition of an individual ARF confers protection against the toxic actions on motor neurons of mutant SOD or mutant TDP43. Identification of the specific Cy/ARF pair that upon disabling is neuroprotective will be the launching pad for insight into mechanisms and potential therapeutic targeting.

抽象的神经退行性疾病（如肌萎缩侧索硬化症）的体外和体内模型硬化症（ALS）让人们得以一睹在以下情况下出错的生物过程：这些疾病。目前的想法表明主要的病理生理过程包括蛋白质错误折叠和积累、内质网应激、功能失调细胞内运输、兴奋性毒性、线粒体功能障碍、神经炎症和 RNA 加工异常。 GTP 酶的 ARF 家族是系统发生学上的一个与膜运输、脂质代谢/信号传导有关的保守蛋白质家族，肌动蛋白重塑和脂滴形成。基于之间的明显重叠 ALS 病理生理学和 ARF 的一些生物学作用，我们想知道 ARF 是否信号传导修改的 ALS 模型。在最近发表的工作中，我们发现阻塞细胞粘连素（“Cy's”，ARF 鸟嘌呤核苷酸交换因子）的活性是神经保护作用。了解这一观察结果的细胞生物学机制是由于 Cy's 和 ARF 的多效性作用，这是有问题的。前进的道路将通过确定该过程中涉及的特定 Cy 和特定 ARF 可以促进这将引导我们了解相关的细胞生物学过程。为此，在具体目标#1中，将进行实验以确定单个 Cy 的抑制是否会带来防止突变型 SOD 或突变型 TDP43 对运动神经元的毒性作用。在具体目标#2中，将进行实验以确定是否抑制个体 ARF 可以保护突变体运动神经元免受毒性作用 SOD 或突变体 TDP43。禁用后识别特定的 Cy/ARF 对神经保护将成为深入了解机制和潜力的发射台治疗靶向。