The Unfolded Protein Response in Ischemic Stroke

摘要 除再灌注外，缺血性卒中是世界范围内导致死亡和长期残疾的主要原因 治疗方面，几乎没有可用的治疗方法。因此，迫切需要新的中风疗法，特别是 那些在大多数中风发生的老年人身上表现出疗效的药物。越来越多的证据表明 基于蛋白质抑制剂的疗法在治疗衰老和/或缺血相关疾病方面具有巨大的潜力 以被破坏的蛋白质组为特征。尤其是未折叠蛋白反应(UPR)，它包括 促进蛋白质平衡恢复的多条适应性反应通路已被越来越多地认识到 作为治疗神经退行性疾病和缺血性疾病的极具前景的靶点。UPR被激活 当蛋白质折叠和成熟的关键细胞器内质网(ER)中的蛋白质组被 心烦意乱，一种叫做内质网应激的情况。UPR的主要目的是恢复细胞蛋白平衡和 促进细胞存活。UPR有3个主要分支，以3个内质网应激感受器蛋白命名：ATF6(激活 转录因子6)、IRE1(肌醇需要酶1)和PERK(蛋白激酶RNA样ER激酶)。它是 众所周知，缺血性卒中引起内质网应激并激活UPR。重要的是，我们的大量数据 证实在急性卒中阶段激活神经元中的UPR具有强烈的神经保护作用 支持UPR在缺血性卒中中的治疗潜力。但是，要发展安全有效的基于UPR的 对于中风的药物干预，我们必须进一步了解1)UPR如何影响其他类型的脑细胞， 尤其是星形胶质细胞--大脑中最丰富的细胞亚型，以及2)UPR调制如何影响Long- 足月卒中结局。因此，这项更新建议的目标是确定星形细胞的作用 单个UPR分支在卒中病理生理学中的作用，并评估靶向UPR的治疗潜力 在中风中使用幼年和老年动物。我们的总体假设是，各个普遍定期审议分支机构 以细胞和阶段特定的方式影响卒中结果，因此必须相应地利用 卒中基于UPR的最佳治疗策略。在我们初步数据的指导下，也受到了令人兴奋的启发 在这一领域的进展，我们将追求3个具体目标：1)确定ATF6 UPR分支在缺血中的作用 2)确定IRE1/XBP1 UPR分支在缺血性卒中中的作用；3)确定IRE1/XBP1 UPR分支在缺血性卒中中的作用 缺血性卒中的PERK UPR分支。拟议的研究具有重要意义，因为我们希望澄清这一角色 卒中时各星形细胞UPR分支的变化，以及药物对UPR的调节作用 论卒中阶段和老龄化背景下的卒中结局。这些知识将是告知 开发基于UPR的新策略旨在提高中风患者的生活质量。

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.