Immune-mediated mechanisms underlying conditioning-induced stroke recovery

调理诱导中风恢复的免疫介导机制

基本信息

批准号：
10348725
负责人：
Sunghee Cho
金额：
$ 59.67万
依托单位：
WINIFRED MASTERSON BURKE MED RES INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348725
关键词：
Ablation Acute Address Adoptive Transfer Animals Area Behavior Brain Brain Edema Brain Injuries CD36 gene Cardiovascular Diseases Cells Chronic Clinical Clinical Protocols Clinical Trials Corpus striatum structure Data Databases Development Event Exposure to Frequencies Gait Genetic Goals Health High Fat Diet Human Image Immune Immune system Immunity Immunologics Impairment Infarction Infiltration Inflammation Inflammatory Inflammatory Response Injury Ischemic Stroke Knockout Mice Knowledge Limb Development Limb structure Mediating Mediator of activation protein Mission Motor Mus Nerve Degeneration Obese Mice Outcome Patient-Focused Outcomes Patients Peripheral Phagocytosis Phase Play Prevention strategy Process Recovery Recovery Support Recovery of Function Research Resolution Role Site Source Splenocyte Stroke Substantia nigra structure Thalamic structure Time Tissues United States National Institutes of Health Wallerian Degeneration acute stroke basal ganglia injury base chronic stroke clinical development conditioning diet-induced obesity disability evidence base expectation functional outcomes gain of function improved improved functioning in vivo limb ischemia macrophage monocyte mouse model neuroinflammation neuron loss neuroprotection physically handicapped post stroke pre-clinical receptor recruit relating to nervous system repaired socioeconomics stroke outcome stroke patient stroke recovery tissue repair translational approach transneuronal degeneration

项目摘要

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.

中风是全球身体残疾的主要原因，也是人类的全球社会经济负担健康。中风引起的脑损伤通常被认为是一种中枢神经系统事件，但损伤进展和修复过程深受外周免疫的影响。肢体缺血调理 [LC] 已被证明可以触发内源性保护现象，提供耐受性和保护预防中风和心血管疾病。由于 LC 是在远离受伤大脑的地方应用的，有益的作用可能是由外周免疫细胞介导的，但数量有限中风后神经和外周免疫系统之间相互作用的研究。致地址由于我们知识的空白，该提案将调查 LC 是否以及如何改变外周免疫系统以及 LC 是否可以改善中风的急性结局和慢性恢复。我们在 C57 中的初步发现小鼠实验表明，LC 将循环单核细胞转变为促炎 [MoPro] 状态。这些发现还表明这种 MoPro 转变不会发生在缺乏 CD36 的小鼠中，CD36 是一种高度炎症受体在单核细胞中表达。此外，中风后应用 LC 可减少梗塞面积、脑肿胀和显着增强慢性中风的运动/步态功能。改进的功能与更少的相关黑质中的神经元损失，这是继发性跨神经元变性的区域在涉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 诱导的功能性损伤中具有有益的作用恢复。因此，我们假设 LC 诱导的 MoPro 转变增强了炎症的消退以 CD36 依赖性方式抑制原发性损伤部位，并通过抵消来促进中风恢复继发性变性。目标 1 将利用功能丧失和获得的研究来确定 MoPro 对 LC 引起的中风结果有好处。在目标 2 中，我们将识别并验证 CD36 作为 LC 诱导的单核细胞转移的上游介质。解决LC增强的体内机制功能结果，目标 3 将研究 LC 是否可以抵消继发性变性中风后的黑质和丘脑。在目标 4 中，我们将确定二次学习的频率和时间来自基底神经节中风患者数据库的黑质和丘脑变性受伤。该项目的顺利完成预计将产生重要的积极影响因为它将为转化的后续发展提供一个基于证据的框架使用 LC 来改善慢性中风功能恢复的策略。