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

描述（由申请人提供）：缺血性卒中目前是美国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， 可以减少损伤或恢复功能，一旦中风发生。在过去的几年里，我们认为中风是一种“神经元疾病”的观点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，即中风确实是一种“全身性”疾病，外周炎症过程在其中起着根本性作用。这种外周免疫应答是中风治疗的靶点，因为减少循环白细胞，特别是单核细胞和中性粒细胞的外周浸润，减少缺血性损伤。转化生长因子活化激酶1（Transforming growth factor activated kinase-1，TAK 1）是丝裂原活化蛋白激酶（mitogen-activated protein kinase kinase kinase，MAP 3 K）家族的一员，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。拟议的工作将使用选择性删除骨髓细胞中的TAK来检查TAK信号传导丢失对中风后炎症的影响。将在TAK 1敲除动物中进行机制研究（目的1）。然后，我们将在老年小鼠（一种临床相关的中风动物模型）中确定抑制TAK的神经保护作用（目的2）。这些探索性研究将有望为脑卒中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.