Determining the role of IRE1alpha in amyotrophic lateral sclerosis

确定 IRE1α 在肌萎缩侧索硬化症中的作用

• 批准号: 8521414
• 负责人: Eric Wang
• 金额: $ 3.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521414
• 关键词: American; Amyotrophic Lateral Sclerosis; Apoptosis; Apoptotic; Automobile Driving; Autopsy; Axon; BAX gene; Body Weight decreased; Caspase; Cell Culture System; Cell Culture Techniques; Cell Death; Cell Line; Cells; Diagnosis; Disease; Down-Regulation; Endoplasmic Reticulum; Ensure; Face; Familial Amyotrophic Lateral Sclerosis; Gene Mutation; Genes; Genetic; Global Change; Homeostasis; Human; Integral Membrane Protein; Knowledge; Laboratories; Lead; Life; Maintenance; Measures; MicroRNAs; Microscopy; Modeling; Molecular Chaperones; Motor Neurons; Movement; Mus; Nerve; Neurodegenerative Disorders; Neurons; Neurosciences; Paralysed; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Population; Proteins; Reporting; Research; Ribonucleases; Role; Sampling; Signal Transduction; Skeletal Muscle; Stress; System; Testing; Therapeutic Intervention; Toxic effect; Transgenic Mice; Translations; Up-Regulation; arm; base; caspase-2; chemical genetics; effective therapy; embryonic stem cell; endoplasmic reticulum stress; gain of function mutation; inhibitor/antagonist; interest; motor neuron development; mouse model; neuron loss; overexpression; prevent; protein folding; protein misfolding; public health relevance; response; superoxide dismutase 1; tool; transcription factor

DESCRIPTION (provided by applicant): Neurodegenerative diseases (NDs) are increasingly prevalent, and approximately a quarter of the US population will suffer from a ND during their life. One such ND is amyotrophic lateral sclerosis (ALS), a fatal disease caused by loss of motor neurons (MNs); at present, approximately 30,000 Americans suffer from this disease. Encouragingly, genetic mutations that cause some forms of familial ALS have been identified; however, no effective treatments for ALS exist. As there is evidence that MNs activate the BAX/BAK-dependent apoptosis pathway during ALS, we tested whether loss of Bax and Bak would be beneficial in a mouse model of ALS. Indeed, deletion of Bax and Bak in neurons slows the loss of motor neurons and delays axon degeneration. Furthermore, it delays the onset of paralysis and weight loss and, excitingly, extends survival. However, as BAX and BAK are difficult to target, identification of their upstream activators in MNs in the context of ALS will e essential in developing new therapies for ALS; one such pathway is the unfolded protein response (UPR). The UPR is triggered when unfolded or misfolded proteins accumulate in the endoplasmic reticulum (ER) of a cell, causing "ER stress." When this occurs, the UPR first attempts to restore ER homeostasis by slowing translation and upregulating genes that increase the ER's protein folding capacity. However, if the stress is too severe, the UPR will trigger apoptosis via activation of BAX and BAK. Importantly, there is accumulating evidence that ER stress-induced toxicity is important in driving MN loss in ALS. We have recently discovered that IRE1?, an important UPR effector, is vital in determining whether the UPR signals survival or apoptosis, and we have created chemical-genetic tools that allow us to control IRE1?'s signaling in both cell lines and live mice. Based on our findings, we propose to determine how IRE1? signals BAX/BAK-dependent apoptosis in MNs and whether inhibition of IRE1?'s apoptotic arm is beneficial in ALS. In parallel, appropriate coursework in neuroscience and microscopy will be taken to ensure robust background knowledge necessary to perform the proposed research.

描述（由申请人提供）：神经退行性疾病（ND）越来越普遍，大约四分之一的美国人口将在其一生中遭受ND。一种这样的ND是肌萎缩性侧索硬化症（ALS），一种由运动神经元（MN）损失引起的致命疾病;目前，大约30，000名美国人患有这种疾病。令人鼓舞的是，已经确定了导致某些形式的家族性ALS的基因突变;然而，还没有有效的治疗ALS的方法。由于有证据表明MN在ALS期间激活BAX/BAK依赖性凋亡途径，我们测试了Bax和巴克的缺失是否在ALS小鼠模型中有益。事实上，神经元中Bax和巴克的缺失减缓了运动神经元的损失并延迟了轴突变性。此外，它还能延缓瘫痪和体重减轻的发生，令人兴奋的是，它还能延长生存期。然而，由于BAX和巴克很难靶向，因此在ALS的背景下鉴定MN中它们的上游激活物对于开发ALS的新疗法至关重要;其中一种这样的途径是未折叠蛋白反应（UPR）。当未折叠或错误折叠的蛋白质在细胞的内质网（ER）中积累时，UPR被触发，引起“ER应激”。当这种情况发生时，UPR首先试图通过减缓翻译和上调增加ER蛋白折叠能力的基因来恢复ER稳态。然而，如果应激太严重，UPR将通过激活BAX和巴克触发细胞凋亡。重要的是，有越来越多的证据表明，ER应激诱导的毒性在ALS中驱动MN损失是重要的。我们最近发现IRE 1？，一种重要的UPR效应器，对于确定UPR是否发出生存或细胞凋亡信号至关重要，我们已经创造了化学遗传工具，使我们能够控制IRE 1？在细胞系和活体小鼠中的信号传导。根据我们的研究结果，我们建议，以确定如何IRE 1？信号BAX/BAK依赖的细胞凋亡在MN和是否抑制IRE 1？的凋亡臂在ALS中是有益的。同时，将采取适当的神经科学和显微镜课程，以确保执行拟议的研究所需的强大的背景知识。