Unraveling Cell Death Mechanisms After Intracerebral Hemorrhage

虽然脑出血（ICH，所有卒中的15-20%）比缺血性卒中更不常见，但在所有卒中类型中，脑出血的死亡率最高（30天时约为50%）。降低ICH死亡率和发病率的治疗选择有限。尽管其对公共卫生的重要性日益增加，但我们对ICH后如何发生永久性大脑损伤并导致死亡和残疾的了解还不完整。鉴于大脑自发修复的能力有限，减少残疾的一个重要而直接的策略是防止神经元的损失，这构成了摆在你面前的建议的基本基础。为了实现这一重要目标，我们必须了解脑细胞如何在脑出血反应中损失的潜在机制。由于神经元具有独特的细胞结构，（控制塔）和一个新兴的轴突（功能类似电话线），可以将神经元细胞体与几英尺外的其他神经元连接起来，重要的是要知道细胞体或轴突中的病理事件，或两者，目前的建议旨在检验脑出血后神经元死亡的机制在细胞体和细胞外基质中的特定假设，轴突是不同的，积极调节，年龄依赖性。这项赠款将利用什么是已知的不同机制和口味的细胞如何死亡，以开发一种新的治疗方法，以减少损伤后ICH。我将使用药理学药物结合高度复杂的电子显微镜来评估细胞在积极死亡时的形态以及如何防止这种情况。此外，使用最先进的分子生物学对潜在治疗靶点的操纵最终将集中在更完整地识别和验证治疗干预的潜在途径上。我上面概述的严格方法经过了时间的考验，并且我已经确定了新的治疗靶点。干预的目标。然而，到目前为止，这种方法还没有用于治疗人类出血性中风，我将在我们的研究中增加两个重要的变量（以前没有检查过），以提高翻译到人类床边的可能性。首先，我假设脑出血后细胞损伤和丢失的机制在细胞体及其相关轴突中有很大不同，我将使用微流体室进行研究。第二，为了解决衰老是否影响细胞体或轴突中细胞死亡机制的问题，我建议使用一种遗传策略，包括在脑神经元中强制表达早老蛋白突变体，通过纳入两个新的变量，通常不包括在ICH研究中，我们预计确定新的和更容易翻译的治疗方法ICH。我们希望这将创造一种新的方法，可以被其他人用来识别和验证ICH卒中治疗的靶点。

Although less common than its ischemic counterpart, intracerebral hemorrhage (ICH, 15-20% of all strokes) has the highest mortality rate among all stroke types (~50% at 30 days). Treatment options for reducing mortality and morbidity for ICH are limited. Despite its growing public health importance, our understanding of how permanent damage to the brain occurs following ICH that fosters mortality and disability is incomplete. Given the limited capacity of the brain to repair spontaneously, an important, immediate strategy for reducing disability is to prevent the loss of neurons and this forms the fundamental basis of the proposal before you.In order to accomplish this important goal, we must understand the underlying mechanisms of how brain cells are lost in response to bleeding in the brain. As neurons have unique cytoarchitectures that involve a cell body (control tower) and an emerging axon (that functions like a telephone line) that can connect neuronal cell bodies with other neurons several feet away, it is important to know whether pathological events in the cell body or the axon, or both, mediate loss of function after ICH.The present proposal seeks to test the specific hypothesis that the mechanisms of neuronal death after intracerebral hemorrhage in the cell body and axons are different, actively regulated, and age-dependent.This grant will leverage what is known about the distinct mechanisms and flavors of how cells die to develop a novel therapeutic approach to reducing injury following ICH. I will use pharmacological drugs in conjunction with highly sophisticated electron microscopy to assess the morphology of cells while they are actively dying and how this can be prevented. Moreover, manipulation of potential therapeutic targets using state-of-the-art molecular biology will ultimately converge on a more complete identification and validation of potential pathways for therapeutic intervention.The rigorous approach I have outlined above is time-tested and I have already identified new targets for intervention. However, as of now, this approach has not delivered to treat human hemorrhagic stroke and I will add two important variables to our studies (not examined before) to enhance the likelihood of translation to the human bedside. First, I hypothesize that mechanisms of cell damage and loss following ICH are largely different in the cell body and its associated axon, which I will investigate using microfluidic chambers. Second, to address the question of whether aging affects the mechanism of cell death in the cell body or axon, I propose to use a genetic strategy involving the forced expression of progerin mutants in brain neurons.By incorporating two new variables not normally included in ICH studies, we anticipate identifying new and more readily translatable therapeutic approaches for ICH. We expect this will create a new approach that could be adapted by others of how to identify and validate targets for ICH stroke therapy.