The Unfolded Protein Response in Ischemic Stroke

摘要 缺血性卒中是世界范围内死亡和长期残疾的主要原因， 治疗，几乎没有治疗方法。因此，迫切需要新的中风疗法，特别是 那些在老年人中表现出疗效的药物，大多数中风发生在老年人中。越来越多的证据表明， 基于蛋白质沉积的疗法在治疗衰老和/或缺血相关疾病中具有巨大的潜力， 其特征在于蛋白质组被破坏。特别地，未折叠蛋白质应答（UPR），其包括 多种适应性反应途径，促进恢复蛋白质稳态，已越来越多地认识到 作为神经变性和缺血性疾病的非常有前途的治疗靶点。普遍定期审议启动 当内质网（ER）中的蛋白质组（蛋白质折叠和成熟的关键细胞器） 一种被称为ER应力的状态普遍定期审议的主要目的是恢复细胞蛋白质稳态， 促进细胞存活。UPR有3个主要分支，以3种ER应激传感器蛋白命名：ATF 6（激活 转录因子6）、IRE 1（肌醇需要酶1）和PERK（蛋白激酶RNA样ER激酶）。是 众所周知，缺血性中风引起ER应激并激活UPR。重要的是，我们的大量数据 证实了急性中风期神经元中UPR的激活具有神经保护作用， 支持UPR在缺血性卒中中的治疗潜力。但是，为了开发安全有效的基于UPR的 在中风的药物干预，我们必须进一步了解1）UPR如何影响其他脑细胞类型， 特别是星形胶质细胞-大脑中最丰富的细胞亚型，以及2）UPR调节如何影响长期- 卒中结局。因此，这项更新建议的目标是确定星形胶质细胞的作用， 卒中病理生理学中的单个UPR分支，并评估靶向UPR的治疗潜力 在中风中使用年轻和年老的动物。我们的总体假设是，普遍定期审议的各个分支机构 以细胞和阶段特异性方式影响中风结果，因此必须相应地加以利用， 最佳的UPR为基础的治疗策略在中风。在我们初步数据的指导下， 为了研究该领域的进展，我们将追求3个具体目标：1）确定ATF 6 UPR分支在缺血性脑损伤中的作用， 中风; 2）确定IRE 1/XBP 1 UPR分支在缺血性中风中的作用; 3）确定IRE 1/XBP 1 UPR分支在缺血性中风中的作用。 缺血性卒中中的PERK UPR分支。拟议的研究是重要的，因为我们希望澄清的作用， 脑卒中中各星形胶质细胞UPR分支的表达，并确定UPR的药理学调节作用 在中风阶段和衰老的背景下中风的结果。这些知识将是告知 开发新的基于UPR的策略，旨在改善卒中患者的生活质量。

Abstract Ischemic stroke is a leading cause of death and long-term disability worldwide, and other than reperfusion therapy, almost no treatment is available. Thus, there is an urgent need for new stroke therapies, particularly those that demonstrate efficacy in the elderly, when most strokes occur. Mounting evidence indicates that proteostasis-based therapeutics have great potential in treating aging- and/or ischemia-related diseases that are characterized by a disrupted proteome. Especially, the unfolded protein response (UPR), which comprises multiple adaptive response pathways that facilitate recovery of proteostasis, has been increasingly recognized as a highly promising therapeutic target for neurodegenerative and ischemic diseases. The UPR is activated when the proteome in the endoplasmic reticulum (ER), a key organelle for protein folding and maturation, is perturbed, a condition called ER stress. The primary purpose of the UPR is to restore cellular proteostasis and promote cell survival. The UPR has 3 major branches, named after 3 ER stress sensor proteins: ATF6 (activating transcription factor 6), IRE1(inositol-requiring enzyme 1), and PERK (protein kinase RNA-like ER kinase). It is well known that ischemic stroke causes ER stress and activates the UPR. Importantly, our extensive data have established that activation of the UPR in neurons during the acute stroke phase is neuroprotective, strongly endorsing the therapeutic potential of the UPR in ischemic stroke. But, to develop safe and effective UPR-based pharmacologic interventions in stroke, we must further know 1) how the UPR affects other brain cell types, especially astrocytes – the most abundant cell subtype in the brain, and 2) how UPR modulation impacts long- term stroke outcome. Thus, the objectives of this renewal proposal are to determine the astrocytic role of the individual UPR branches in stroke pathophysiology, and to assess the therapeutic potential of targeting the UPR in stroke using young and aged animals. Our overarching hypothesis is that the individual UPR branches influence stroke outcome in a cell- and phase-specific manner and thus, must be harnessed accordingly for optimal UPR-based therapeutic strategies in stroke. Guided by our preliminary data, and also inspired by exciting advances in the field, we will pursue 3 specific aims: 1) Determine the role of the ATF6 UPR branch in ischemic stroke; 2) Determine the role of the IRE1/XBP1 UPR branch in ischemic stroke; 3) Determine the role of the PERK UPR branch in ischemic stroke. The proposed research is significant because we expect to clarify the role of each astrocytic UPR branch in stroke, and to determine the effects of pharmacologic modulation of the UPR on stroke outcome in the context of stroke phase and aging. Such knowledge will be fundamental to informing the development of new UPR-based strategies aimed to improve quality of life for stroke patients.