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

摘要 在美国，每年有100多万人受到心脏骤停或中风引起的脑缺血的影响， 可能会带来毁灭性的后果。缺血致残是家庭和医疗保健的主要负担 系统。随着我们人口老龄化，这个问题将产生更大的影响，因为年龄是关键风险。 导致心脏骤停和缺血性中风的因素。因此，迫切需要界定年龄在结果中的作用。 在脑缺血/中风后，为了开发为老年人脑缺血/中风量身定做的新治疗策略 病人。缺血是一种严重的代谢应激形式，激活了病理和保护途径- 方式。当保护通路占主导地位时，结果会得到改善。老年患者术后康复情况不佳 脑缺血事件意味着衰老与大脑激活支持生存的能力下降有关 脑缺血发作后的通路。事实上，几条促进生存的通路的激活明显受损。 在衰老的大脑中。这在蛋白质的O-连接β-N-乙酰氨基葡萄糖(O-GlcNAc)修饰中最为明显，a 翻译后修饰和在各种应激条件下有效的促进生存的途径。虽然它是 已知年龄是脑缺血/卒中后预后不良关键危险因素，并激活保护性 途径改善预后，我们还不知道如何应用这种知识来改善老年人的预后 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 在一次缺血事件之后。这里的目标是确定为什么对缺血应激的抵抗力在 老化的大脑，并制定增加抵抗力的策略。我们的中心假设是，衰老与- 大脑在应对压力时激活保护通路的能力下降，以及 促进这些途径可以提高对压力的耐受性。根据脑缺血实验的结果 老年动物，并使用我们新的神经元特异性转基因和基因敲除小鼠模型，我们将测试我们的hy- 通过追求以下具体目标进行假说：1)确定与年龄相关的衰退的机制 在短暂性前脑缺血时，大脑激活O-GlcNAc修饰并发展Res的能力。 提示策略；2)确定增强O-GlcNAc修饰在多大程度上改善中风预后 大脑老化。拟议的项目是创新的，因为我们将采用一种新的方法来保护神经 促进内源性保护途径，与目前干扰 病理途径；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O-GlcNAc通路在脑缺血/卒中中的作用。这项拟议的研究具有重要意义，因为 我们预计，这种神经保护的新方法，专门为增加老年人的抵抗力而量身定做的 脑缺血的挑战，将是改善老年患者预后的重大突破 在一次缺血事件之后。

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.