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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.

摘要