Cytoprotection with Autologous Mononuclear Cells for Stroke

描述（由申请人提供）：细胞治疗已成为一种潜在的新治疗方法，可减少缺血性卒中后的损伤和改善预后。一些研究表明，来自骨髓的单核细胞（MNCs）是安全的，并能促进动物中风模型的恢复。这项拨款提案旨在确定跨国公司使用各种体外和体内缺血性中风模型减少神经功能缺陷的具体机制。我们的初步数据表明，MNCs具有细胞保护作用，可以减少缺血后大脑的促炎症反应。在Specific Aim 1中，我们首先将确定跨国公司中的哪些细胞群对减少中风后的神经功能缺损、病变大小和促炎反应至关重要。在Specific Aim 2中，我们将验证跨国公司释放细胞因子、IL-10和IGF-1的假设，这些细胞因子导致小胶质细胞的神经保护和调节。Aim 2A将重点研究这两种细胞因子由跨国公司分泌，在体外缺氧模型中直接保护神经元，在中风动物模型中直接减轻损伤。Aim 2B提出了mnc激活和改变脑卒中后小胶质细胞成为抗炎和神经保护细胞的假设。我们假设IL-10和IGF-1是mnc调节脑卒中后小胶质细胞抗炎和神经保护作用的关键因素。我们提出的研究将是阐明介导跨国公司在缺血后大脑中的保护作用的具体途径的第一步，对于将跨国公司作为缺血性中风的潜在治疗方法至关重要，缺血性中风是一种巨大的公共卫生需求，需要更多和改进的治疗方法。

DESCRIPTION (provided by applicant): Cell therapy has emerged as a potential new treatment to reduce injury and improve outcome after ischemic stroke. Several studies have demonstrated that mononuclear cells (MNCs) from bone marrow are safe and enhance recovery in animal stroke models. This grant proposal aims to define specific mechanisms by which MNCs reduce neurological deficits using a variety of in vitro and in vivo models of ischemic stroke. Our preliminary data indicate that MNCs are cytoprotective and reduce pro-inflammatory responses in the post-ischemic brain. In Specific Aim 1, we first will determine which cell populations within MNCs are critical to reduce neurological deficits, lesion size, and pro-inflammatory responses after stroke. In Specific Aim 2, we will test the hypothesis that MNCs release the cytokines, IL-10 and IGF-1, which lead to neuroprotection and modulation of microglia. Aim 2A will focus on the hypothesis that both cytokines, secreted by MNCs, directly protect neurons in in vitro models of hypoxia and directly reduce injury in an animal model of stroke. Aim 2B addresses the hypothesis that MNCs activate and change microglia to become anti-inflammatory and neuroprotective after stroke. We hypothesize that IL-10 and IGF-1 are key factors in the capacity of MNCs to modulate the anti-inflammatory and neuroprotective effects of microglia after stroke. Our proposed studies would be the first step to elucidate specific pathways mediating the protective effects of MNCs in the post-ischemic brain and are critical to develop MNCs as a potential treatment for ischemic stroke, a condition for which there is an enormous public health need for more and improved therapies. PUBLIC HEALTH RELEVANCE: Stroke is the leading cause of adult disability but there is only one approved therapy with limited effectiveness for this devastating condition. Cellular therapy is a promising new approach to improve stroke recovery. This application proposes to define underlying mechanisms by which autologous bone marrow mononuclear cells improve outcome after stroke. The data from these proposed experiments are essential to better develop this new therapeutic approach to enhance recovery from stroke.