Cytoprotection with Autologous Mononuclear Cells for Stroke

描述(由申请人提供)：细胞疗法已经成为一种潜在的新疗法，可以减少缺血性中风后的损伤并改善预后。多项研究表明，在动物中风模型中，从骨髓中提取的单个核细胞(MNC)是安全的，并能促进康复。这项拨款提案旨在确定跨国公司通过使用各种体外和体内缺血性中风模型来减少神经功能缺陷的具体机制。我们的初步数据表明，单核细胞具有细胞保护作用，可以减少脑缺血后的促炎反应。在具体目标1中，我们首先将确定MNC中的哪些细胞群对于减少中风后的神经功能缺陷、病变大小和促炎反应至关重要。在特定的目标2中，我们将检验MNC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。目的：在体外缺氧模型中，单核细胞分泌的两种细胞因子对神经元具有直接保护作用，在卒中动物模型中，这两种细胞因子可直接减轻损伤。目的2B提出中风后单核细胞激活并改变小胶质细胞以达到抗炎和神经保护作用的假说。我们推测，IL-10和IGF-1是MNCs调节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MNCs在脑缺血后保护作用的具体途径的第一步，并且对于将MNCs发展为一种潜在的缺血性中风治疗方法至关重要，对于这种情况，公共卫生需要更多和更好的治疗方法。 公共卫生相关性：中风是成人残疾的主要原因，但只有一种被批准的治疗方法对这种毁灭性的疾病效果有限。细胞疗法是提高卒中康复的一种很有前途的新方法。这项应用建议确定自体骨髓单个核细胞改善卒中后预后的潜在机制。这些拟议实验的数据对于更好地开发这一新的治疗方法以促进中风的康复至关重要。

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.