Cytoprotection with Autologous Mononuclear Cells for Stroke

描述（由申请人提供）：细胞疗法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并改善预后。几项研究已经证明，来自骨髓的单核细胞（MNCs）是安全的，并在动物中风模型中促进恢复。这项资助计划旨在通过各种缺血性卒中的体外和体内模型来确定MNCs减少神经功能缺损的具体机制。我们的初步数据表明，MNCs是细胞保护性的，并减少缺血后大脑中的促炎反应。在具体目标1中，我们首先将确定MNCs中的哪些细胞群对减少卒中后的神经功能缺损、病变大小和促炎反应至关重要。在具体目标2中，我们将检验这样的假设：MNCs释放细胞因子IL-10和IGF-1，从而导致小胶质细胞的神经保护和调节。目的2A将集中于这样的假设，即由MNCs分泌的两种细胞因子在缺氧的体外模型中直接保护神经元并且在中风的动物模型中直接减少损伤。目的2B提出了MNCs激活和改变小胶质细胞以在中风后变得抗炎和神经保护的假设。我们假设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能力的关键因素。我们提出的研究将是阐明介导MNCs在缺血后脑中保护作用的特定途径的第一步，并且对于开发MNCs作为缺血性卒中的潜在治疗至关重要，缺血性卒中是一种巨大的公共卫生需要更多和改进的治疗方法的疾病。 公共卫生相关性：中风是成人残疾的主要原因，但只有一种批准的治疗方法对这种毁灭性的疾病有效性有限。细胞疗法是改善中风恢复的一种有前途的新方法。本申请旨在确定自体骨髓单个核细胞改善卒中后结局的潜在机制。来自这些拟议实验的数据对于更好地开发这种新的治疗方法以促进中风的恢复至关重要。

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.