TWEAK-Induced Ischemic Neuronal Death

描述(申请人提供)：肿瘤坏死因子样弱凋亡诱导物(TWEEP)是肿瘤坏死因子超家族(TNFSF)的成员，通过与称为成纤维细胞生长因子诱导14(Fn14)的细胞表面受体结合作用于反应性细胞。TWEEP和Fn14已在非缺血条件下在神经元中检测到表达，大脑中动脉阻塞(MCAO)或缺氧-葡萄糖剥夺(OGD)条件下的神经元培养都导致该细胞因子及其受体的表达显著增加。我们已经证明，TWEEP与Fn14结合可诱导NF-β活化和神经细胞死亡，而用可溶性Fn14-Fc诱骗受体或Fn14基因缺陷抑制TWEAM活性可减少缺血损伤的体积和保护缺血半暗带的面积。在本研究中，我们假设脑缺血时TWEEP和Fn14之间的相互作用通过caspase依赖和非依赖机制诱导缺血半暗带区神经细胞死亡。更具体地说，我们假设MCAO后TWEEP与Fn14的结合通过激活“内在的”和“外在的”凋亡途径，以及通过依赖于核因子B激活多(ADP-核糖)聚合酶-1(PARP-1)和核转位的凋亡诱导因子(AIF)来诱导细胞死亡。此外，根据体内最先进的神经成像技术的评估，MCAO后使用TWEK活性抑制剂治疗可以减少脑缺血诱导的神经元死亡，并改善缺血组织的命运。这些都是与临床相关的研究，可能会导致一种新的治疗方法，以防止缺血性中风患者的神经细胞死亡。

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.