Determining the role of IRE1alpha in amyotrophic lateral sclerosis

描述(申请人提供)：神经退行性疾病(NDS)日益流行，大约四分之一的美国人口将在他们的一生中遭受ND的折磨。其中一种ND是肌萎缩侧索硬化症(ALS)，这是一种由运动神经元丢失(MNS)引起的致命疾病；目前，大约有30,000美国人患有这种疾病。令人鼓舞的是，导致某些形式的家族性肌萎缩侧索硬化症的基因突变已经被识别出来；然而，目前还没有有效的治疗方法。由于有证据表明MNS在ALS过程中激活了Bax/BAK依赖的细胞凋亡途径，我们测试了Bax和Bak的缺失是否对ALS小鼠模型有利。事实上，神经元中Bax和Bak的缺失减缓了运动神经元的丧失，并延缓了轴突的退化。此外，它还可以延缓瘫痪和体重减轻的发生，令人兴奋的是，它还延长了存活期。然而，由于Bax和BAK很难靶向，在ALS的背景下识别它们在MNS中的上游激活子对于开发ALS的新疗法至关重要；其中一个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就会被触发，从而导致“内质网应激”。当这种情况发生时，UPR首先试图通过减缓翻译和上调增加内质网蛋白质折叠能力的基因来恢复内质网的动态平衡。然而，如果应激过度，UPR将通过激活Bax和BAK来触发细胞凋亡。重要的是，越来越多的证据表明，内质网应激诱导的毒性在肌萎缩侧索硬化症的MN丢失中起重要作用。我们最近发现，IRE1？是一个重要的UPR效应因子，在决定UPR信号是生存还是凋亡方面起着至关重要的作用，我们已经创造了化学遗传学工具，使我们能够在细胞系和活着的小鼠中控制IRE1？‘S信号转导。基于我们的发现，我们建议确定IRE1？如何在MNS中信号转导bax/bak依赖的凋亡，以及抑制IRE1？S的凋亡臂在ALS中是否有益。同时，将采取适当的神经科学和显微镜方面的课程，以确保进行拟议的研究所需的坚实的背景知识。

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.