Neuroprotective Potential of TGF-beta Activated Kinase Inhibition in Acute Stroke

描述(申请人提供)：在美国，缺血性中风是导致持续性神经功能障碍的最常见原因。尽管付出了相当大的努力，但还没有一种治疗方法 一旦中风发生，可以减少伤害或恢复功能。在过去的几年里，我们对中风的看法已经转变为中风是一种神经血管疾病的概念，最近又转变为一种新的理论，即中风是一种真正的“全身性”疾病，在这种疾病中，外周炎症过程起着基础性作用。这种外周免疫反应是中风治疗的目标，因为减少外周循环白细胞的渗透，特别是单核细胞和中性粒细胞，可以减少缺血性损伤。转化生长因子�激活的蛋白激酶-1是丝裂原活化蛋白激酶家族的成员，近年来被认为是脑损伤先天免疫反应中不可或缺的信号分子。这项拟议的工作将通过选择性删除髓系细胞中的TAK来研究TAK信号的丢失在卒中后炎症中的作用。将在TAK1基因敲除动物中进行机制研究(目标1)。然后，我们将确定药物抑制TAK在老年小鼠中的神经保护效果，TAK是一种临床相关的中风动物模型(目标2)。这些探索性研究有望为中风患者的治疗干预确定新的生物靶点。

DESCRIPTION (provided by applicant): Ischemic stroke is now the most frequent cause of persistent neurologic disability in the US. Despite considerable effort there are no therapies that can reduce injury or restore function once a stroke occurs. Over the past several years, our view of stroke as a "neuronal disease" has been transformed into the concept of stroke as a "neurovascular" disease, and more recently into the novel theory that stroke is truly a "systemic" disease in which peripheral inflammatory processes play a fundamental role. This peripheral immune response is a target for stroke therapy, as reducing peripheral infiltration of circulating leukocytes, specifically monocytes and neutrophils, decreases ischemic injury. Transforming growth factor � activated kinase-1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family has been recently recognized as an indispensible signaling molecule in the innate immune response to brain injury. The proposed work will examine the effects of loss of TAK signaling on post-stroke inflammation using selective deletion of TAK in myeloid cells. Mechanistic studies will be performed in TAK1 knockout animals (Aim 1). We will then determine the neuroprotective efficacy of pharmacologically inhibiting TAK in aged mice, a clinically relevant animal model for stroke (Aim 2). These exploratory studies will hopefully identify new biological targets for therapeutic intervention for patients with stroke.