TWEAK-Induced Ischemic Neuronal Death

描述（由申请人提供）：肿瘤坏死因子样细胞凋亡弱诱导剂（TWEAK）是肿瘤坏死因子超家族（TNFSF）的一员，通过结合被称为成纤维细胞生长因子诱导14 （Fn14）的细胞表面受体作用于应答细胞。在非缺血条件下，在神经元中检测到TWEAK和Fn14的表达，无论是大脑中动脉闭塞（MCAO）还是神经元培养物暴露于氧-葡萄糖剥夺（OGD）条件下，都会导致该细胞因子及其受体的表达显著增加。我们已经证明，TWEAK与Fn14的结合可诱导NF-？B活化和神经元细胞死亡，以及MCAO后通过可溶性Fn14- fc诱饵受体或Fn14基因缺陷处理抑制TWEAK活性，可减少缺血性病变的体积并保护缺血半暗区。在本研究中，我们假设在脑缺血过程中，TWEAK和Fn14之间的相互作用通过caspase依赖性和非依赖性机制诱导缺血半暗带区域的神经元细胞死亡。更具体地说，我们假设在MCAO后，TWEAK与Fn14的结合通过激活“内在”和“外在”凋亡途径以及NF-？与凋亡诱导因子（AIF）核易位相关的聚（adp -核糖）聚合酶-1 （PARP-1）的b依赖性激活。此外，根据体内最先进的神经成像技术评估，MCAO后使用TWEAK活性抑制剂治疗可减少脑缺血诱导的神经元死亡，并改善缺血组织的命运。这些与临床相关的研究可能会导致一种新的治疗方法来预防缺血性卒中患者的神经元细胞死亡。公共卫生相关性：缺血性卒中发病后早期，细胞因子TWEAK及其受体Fn14的表达增加。TWEAK与Fn14结合可诱导神经元死亡。本应用的重点是研究TWEAK诱导细胞死亡的机制，以及使用TWEAK活性抑制剂作为预防急性缺血性卒中期间神经元死亡的潜在治疗策略。

DESCRIPTION (provided by applicant): Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily (TNFSF) that acts on responsive cells via binding to a cell surface receptor known as fibroblast growth factor-inducible 14 (Fn14). TWEAK and Fn14 expression has been detected under non-ischemic conditions in neurons, and either middle cerebral artery occlusion (MCAO) or exposure of neuronal cultures to oxygen-glucose deprivation (OGD) conditions results in a significant increase in the expression of this cytokine and its receptor. We have demonstrated that the binding of TWEAK to Fn14 induces NF-?B activation and neuronal cell death and that inhibition of TWEAK activity following MCAO either by treatment with a soluble Fn14-Fc decoy receptor or genetic deficiency of Fn14 decreases the volume of the ischemic lesion and protects the area of ischemia penumbra. In this proposal we hypothesize that the interaction between TWEAK and Fn14 during cerebral ischemia induces neuronal cell death in the area of ischemic penumbra via caspase- dependent and -independent mechanisms. More specifically, we postulate that the binding of TWEAK to Fn14 following MCAO induces cell death by activation of the "intrinsic" and "extrinsic" apoptotic pathways, as well as by NF-?B-dependent activation of poly(ADP-ribose) polymerase-1 (PARP-1) with nuclear translocation of the apoptosis-inducing factor (AIF). Moreover, treatment with inhibitors of TWEAK activity after MCAO decreases cerebral ischemia-induced neuronal death and improves the fate of the ischemic tissue as evaluated by in vivo state-of-the-art neuroimaging techniques. These are clinically-relevant studies likely to result in a new therapeutic approach to prevent neuronal cell death in patients with ischemic stroke. PUBLIC HEALTH RELEVANCE: Early after the onset of ischemic stroke there is an increase in the expression of the cytokine TWEAK and its receptor Fn14. The binding of TWEAK to Fn14 induces neuronal death. This application focuses on the study of the mechanism whereby TWEAK induces cell death and the use of inhibitors of TWEAK activity as a potential therapeutic strategy to prevent neuronal death during acute ischemic stroke.