The Unfolded Protein Response in Ischemic Stroke

缺血性中风中未折叠的蛋白质反应

基本信息

批准号：
10538594
负责人：
Wei Yang
金额：
$ 40.25万
依托单位：
DUKE UNIVERSITY
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：
2016-09-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538594
关键词：
ATF6 gene Acute Affect Aging Animals Astrocytes Blood - brain barrier anatomy Brain Cause of Death Cell Survival Cells Cerebrovascular Circulation Chronic Cicatrix Data Development Disease Elderly Endoplasmic Reticulum Enzymes Event Functional disorder Health Homeostasis Impairment Individual Inositol Intervention Ischemia Ischemic Stroke Knock-in Mouse Knowledge Learning MAPK3 gene Maintenance Mission Mus Names Nerve Degeneration Nervous System Physiology Neurons Organelles Outcome Pathologic Pathway interactions Phase Phenotype Phosphotransferases Process Protein Kinase Proteins Proteome Public Health Quality of life RNA Recovery Recovery of Function Regulation Reperfusion Therapy Research Role Shapes Signal Transduction Stroke Synaptic plasticity Therapeutic United States National Institutes of Health Work XBP1 gene acute stroke aged astrogliosis biological adaptation to stress brain cell cell type clinically significant disability druggable target endoplasmic reticulum stress gain of function healing improved insight long term recovery loss of function mouse genetics neural circuit neuroprotection neurotoxic novel novel therapeutic intervention pharmacologic post stroke preservation protein folding proteostasis response sensor sex stroke model stroke outcome stroke patient stroke recovery stroke therapy therapeutic target tool translatome

ATF6 gene Acute Affect Aging Animals Astrocytes Blood - brain barrier anatomy Brain Cause of Death Cell Survival Cells Cerebrovascular Circulation Chronic Cicatrix Data Development Disease Elderly Endoplasmic Reticulum Enzymes Event Functional disorder Health Homeostasis Impairment Individual Inositol Intervention Ischemia Ischemic Stroke Knock-in Mouse Knowledge Learning MAPK3 gene Maintenance Mission Mus Names Nerve Degeneration Nervous System Physiology Neurons Organelles Outcome Pathologic Pathway interactions Phase Phenotype Phosphotransferases Process Protein Kinase Proteins Proteome Public Health Quality of life RNA Recovery Recovery of Function Regulation Reperfusion Therapy Research Role Shapes Signal Transduction Stroke Synaptic plasticity Therapeutic United States National Institutes of Health Work XBP1 gene acute stroke aged astrogliosis biological adaptation to stress brain cell cell type clinically significant disability druggable target endoplasmic reticulum stress gain of function healing improved insight long term recovery loss of function mouse genetics neural circuit neuroprotection neurotoxic novel novel therapeutic intervention pharmacologic post stroke preservation protein folding proteostasis response sensor sex stroke model stroke outcome stroke patient stroke recovery stroke therapy therapeutic target tool translatome

展开

项目摘要

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.

抽象的缺血性中风是全球死亡和长期残疾的主要原因，除了再灌注以外治疗，几乎没有治疗。那迫切需要新的中风疗法，特别是那些在大多数笔触都发生时在古老的效率中表现出效率的人。越来越多的证据表明基于蛋白质的治疗具有巨大的潜力，可以治疗与缺血有关的疾病以破坏的蛋白质组为特征。尤其是，未展开的蛋白质反应（UPR）越来越多地认识作为神经退行性和缺血性疾病的高度有希望的治疗靶标。 UPR被激活当内质网中的蛋白质组（ER）（用于蛋白质折叠和成熟的关键细胞器）是扰动，一种称为ER应力的疾病。 UPR的主要目的是恢复细胞蛋白抑制剂和促进细胞存活。 UPR有3个主要分支，以3个ER应力传感器蛋白命名：ATF6（激活）转录因子6），IRE1（肌醇征用酶1）和PERK（蛋白激酶RNA样ER激酶）。这是众所周知，缺血性中风会导致ER应力并激活UPR。重要的是，我们的广泛数据有确定在急性中风期神经元中UPR的激活是神经保护性的，强烈认可UPR在缺血性中风中的治疗潜力。但是，开发安全有效的基于UPR 药理学干预中风，我们必须进一步知道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调制如何影响长期术语中风结果。这就是该更新提案的目标是确定中风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动物和老年动物。我们的总体假设是单个UPR分支机构以细胞和相位特异性的方式影响中风结果，因此必须相应利用中风的最佳基于UPR的治疗策略。以我们的初步数据为指导，也受到激动人心的启发该领域的进步，我们将追求3个具体目标：1）确定ATF6 UPR分支在缺血性的作用中风; 2）确定IRE1/XBP1 UPR分支在缺血性中风中的作用； 3）确定缺血性中风中的PERK UPR分支。拟议的研究很重要，因为我们希望澄清角色中风中的每个星形细胞UPR分支，并确定UPR的药理调制的影响在中风阶段和衰老的背景下进行中风结果。这样的知识将是通知新的基于UPR的策略的制定旨在改善中风患者的生活质量。