Effect of Aging on Brain Ischemia/Stroke Outcome; Pathways, Mechanisms, and Rescue

衰老对脑缺血/中风结果的影响；

• 批准号: 9158636
• 负责人: WULF PASCHEN
• 金额: $ 34.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9158636
• 关键词: Accounting; Affect; Age; Aging; Animals; Attention; Brain; Brain Diseases; Brain Injuries; Brain Ischemia; Cells; Cues; Data; Development; Elderly; Event; Family; Fostering; Glucosamine; Goals; Health; Healthcare Systems; Heart; Heart Arrest; Impairment; Induced Heart Arrest; Ischemia; Ischemic Stroke; Knockout Mice; Knowledge; Learning; Link; Metabolic stress; Mission; Modification; Mus; Neurons; Outcome; Pathway interactions; Patients; Play; Population; Post-Translational Protein Processing; Prosencephalon; Proteins; Public Health; Recovery; Reperfusion Injury; Reporting; Research; Research Personnel; Resistance; Resuscitation; Risk Factors; Role; Stress; Stroke; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; United States National Institutes of Health; Work; abstracting; acute stroke; age effect; age related; aged; aging brain; base; biological adaptation to stress; brain tissue; disability; effective therapy; improved; improved outcome; innovation; mouse model; neuroprotection; novel; novel strategies; novel therapeutic intervention; novel therapeutics; older patient; research study; response; sensor; stroke therapy

Abstract Brain ischemia induced by cardiac arrest or stroke affects over one million people in the US every year, and can have devastating consequences. Ischemia-induced disability is major burden on families and healthcare systems. This problem will have an even greater impact as our population ages, because age is the key risk factor for cardiac arrest and ischemic stroke. Thus, there is an urgent need to define the role of age in outcome after brain ischemia/stroke in order to develop novel therapeutic strategies tailored for elderly ischemia/stroke patients. Ischemia is a severe form of metabolic stress that activates both pathological and protective path- ways. Outcome is improved when protective pathways dominate. The poor recovery of elderly patients after an ischemic event implies that aging is associated with a decline in the brain's capacity to activate pro-survival pathways after an ischemic episode. Indeed, activation of several pro-survival pathways is markedly impaired in aged brains. This is most evident in O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins, a post-translational modification and potent pro-survival pathway in a variety of stress conditions. While it is known that age is a key risk factor for poor outcome after brain ischemia/stroke and that activation of protective pathways improves outcome, we do not yet known how to apply this knowledge to improve outcome in aged patients who have suffered brain ischemia/stroke. Our long-term goal is to improve outcome in elderly patients after an ischemic event. The objective here is to determine why resistance to ischemic stress is decreased in aged brains, and to develop strategies to increase resistance. Our central hypothesis is that aging is associat- ed with a decline in the brain's capacity to activate protective pathways in response to stress conditions, and that boosting these pathways increases tolerance to stress. Based on results from ischemia experiments on aged animals, and using our new neuron-specific transgenic and knockout mouse models, we will test our hy- pothesis by pursuing the following specific aims: 1) Determine mechanisms underlying the age-related decline in the ability of the brain to activate O-GlcNAc modification upon transient forebrain ischemia and develop res- cue strategies; 2) Determine the extent to which boosting O-GlcNAc modification improves stroke outcome in aged brains. The proposed project is innovative because we will take a novel approach to neuroprotection that boosts an endogenous protective pathway, a substantial departure from current approaches that interfere with pathological pathways; we will focus on brain ischemia in aged animals; and importantly, this will the first study to investigate the O-GlcNAc pathway in brain ischemia/stroke. The proposed research is significant because we expect that this new approach to neuroprotection, specifically tailored to increase the resistance of aged brains to an ischemic challenge, will be a major breakthrough toward improving outcomes in elderly patients after an ischemic event.

摘要 心脏骤停或中风引起的脑缺血每年影响美国超过一百万人， 会造成毁灭性的后果缺血性残疾是家庭和医疗保健的主要负担 系统.随着人口老龄化，这一问题的影响将更大，因为年龄是关键风险 心脏骤停和缺血性中风的危险因素因此，迫切需要确定年龄在结果中的作用 以开发针对老年缺血/卒中的新型治疗策略 患者缺血是一种严重的代谢应激形式，激活病理和保护途径- 的方式当保护途径占主导地位时，结果会得到改善。老年患者在接受治疗后恢复不佳， 缺血性事件意味着衰老与大脑激活促生存能力的下降有关 脑缺血发作后的神经通路事实上，几种促生存途径的激活明显受损 在老年人的大脑中。这在蛋白质的O-连接β-N-乙酰葡糖胺（O-GlcNAc）修饰中最为明显， 翻译后修饰和在各种应激条件下的有效促存活途径。虽然 已知年龄是脑缺血/中风后不良结果关键危险因素， 通路改善结果，我们还不知道如何应用这些知识来改善老年人的结果。 患有脑缺血/中风的患者。我们的长期目标是改善老年患者的预后 在缺血性事件之后。本研究的目的是确定为什么缺血性应激的抵抗力下降， 老化的大脑，并制定战略，以增加抵抗力。我们的中心假设是衰老是相关的- 艾德，大脑在应激条件下激活保护通路的能力下降， 促进这些途径可以提高对压力的耐受性。根据缺血实验的结果， 老年动物，并使用我们新的神经元特异性转基因和敲除小鼠模型，我们将测试我们的hy- 通过追求以下具体目标来假设：1）确定与年龄相关的衰退的潜在机制 在短暂性前脑缺血时大脑激活O-GlcNAc修饰的能力和发生再灌注的能力中， 提示策略; 2）确定加强O-GlcNAc修饰改善卒中结局的程度， 老化的大脑该项目是创新的，因为我们将采取一种新的神经保护方法， 增强了内源性保护途径，这与目前的方法有很大不同， 病理通路;我们将专注于老年动物的脑缺血;重要的是，这将是第一个研究 探讨脑缺血/卒中中O-GlcNAc通路的变化。这项研究意义重大，因为 我们希望这种新的神经保护方法，特别是针对增加老年人的抵抗力， 大脑缺血的挑战，将是改善老年患者预后的重大突破 在缺血性事件之后。