Immune-Mediated Mechanisms Underlying Conditioning-Induced Stroke Recovery

中风是世界范围内导致肢体残疾的主要原因，也是全球人类的社会经济负担 健康。中风引起的脑损伤通常被认为是一种专门的中枢神经系统事件，但损伤进展 而修复过程深受外周免疫力的影响。肢体缺血条件作用[LC] 已经被证明触发了一种内源性保护现象，这种现象提供了耐受和保护 对抗中风和心血管疾病。因为LC是从受伤的大脑远程实施的，所以它的 有益的影响可能是由外周免疫细胞介导的，但只有有限的数量。 研究中风后神经和外周免疫系统之间的相互作用。致信地址 在我们知识上的差距，这项提议将调查LC是否以及如何改变外周免疫系统 LC是否能改善卒中患者的急性转归和慢性康复。我们在C57中的初步发现 小鼠的实验表明，LC会将循环中的单核细胞转变为促炎症状态。这些发现还包括 表明这种MoPro转变不会发生在缺乏CD36的小鼠身上，CD36是一种高度炎性受体 在单核细胞中表达。此外，卒中后应用LC可减少脑梗塞范围、脑肿胀和 显著增强慢性中风患者的运动/步态功能。改进的功能与更少的 黑质神经元丢失，这是一个继发性跨神经元变性的区域 在累及纹状体的中风中观察到。尽管MoPro在促进 急性组织损伤，我们的观察表明MoPro在LC诱导的功能障碍中具有有益的作用 恢复。因此，我们假设LC诱导的MoPro移位增强了炎症在 以CD36依赖的方式在原发损伤部位，并通过对抗促进中风恢复 继发性退行性变。目标1将使用功能损失和功能获得研究来确定 MoPro用于LC诱导的卒中结局的益处。在目标2中，我们将识别和验证CD36作为 LC诱导单核细胞移位的上游介体。探讨LC增强的体内机制 功能结果，目标3将调查LC是否能抵消脑内继发性退变 卒中后黑质和丘脑。在目标4中，我们将确定次要的频率和时间 基底节卒中患者数据库中黑质和丘脑的变性 受伤。预计该项目的顺利完成将产生重要和积极的影响 因为它将为后续的翻译开发提供一个基于证据的框架 应用LC促进慢性卒中患者功能恢复的策略。

Stroke is the leading cause of physical disability worldwide and is a global socioeconomic burden to human health. Brain injury from stroke is typically considered an exclusively CNS event, but injury progression and repair processes are profoundly influenced by peripheral immunity. Ischemic Limb Conditioning [LC] has been shown to trigger an endogenous protective phenomenon that provides tolerance and protection against stroke and cardiovascular diseases. Because LC is applied remotely from the injured brain, its beneficial effects may be mediated by peripheral immune cells, but there have been only a limited number of studies into interactions between the nervous and peripheral immune systems after stroke. To address the gap in our knowledge, this proposal will investigate if and how LC alters the peripheral immune system and whether LC improves acute outcome and chronic recovery in stroke. Our preliminary findings in C57 mice show that LC shifts circulating monocytes to a pro-inflammatory [MoPro] state. These findings also show that this MoPro shift does not occur in mice deficient for CD36, an inflammatory receptor highly expressed in monocytes. Moreover, post-stroke application of LC reduces infarct size, brain swelling, and profoundly enhances motor/gait function in chronic stroke. The improved function is associated with less neuronal loss in the substantia nigra, an area where secondary transneuronal degeneration has been observed in stroke involving the striatum. Despite the established detrimental role of MoPro in promoting acute tissue damage, our observations indicate that MoPro has a beneficial role in LC-induced functional recovery. Thus, we hypothesize that the LC-induced MoPro shift enhances resolution of inflammation at the primary injury site in a CD36-dependent manner, and promotes stroke recovery by counteracting secondary degeneration. Aim 1 will use loss- and gain-of-function studies to establish the critical role of MoPro for LC-induced benefits in stroke outcome. In Aim 2, we will identify and validate CD36 as an upstream mediator of the LC-induced monocyte shift. To address in vivo mechanism of LC-enhanced functional outcome, Aim 3 will investigate whether LC counteracts secondary degeneration in the substantia nigra and thalamus after stroke. In Aim 4, we will establish the frequency and time of secondary degeneration in the substantia nigra and thalamus from databases of stroke patients with basal ganglia injury. The successful completion of this project is expected to have an important and positive impact because it will provide an evidence-based framework for the subsequent development of translational strategies to use LC in order to improve functional recovery in chronic stroke.