TWEAK-Induced Ischemic Neuronal Death

TWEAK 诱导的缺血性神经元死亡

• 批准号: 8423058
• 负责人: Manuel Salvador Yepes
• 金额: $ 31.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423058
• 关键词: Acute; Adaptor Signaling Protein; Animal Model; Apoptosis Promoter; Apoptotic; Area; Binding; Caspase; Cell Death; Cell Death Inhibition; Cell Surface Receptors; Cells; Cerebral Ischemia; Cessation of life; Clinical; Fibroblast Growth Factor; Genetic; Glucose; Health; Ischemia; Ischemic Penumbra; Ischemic Stroke; Mediating; Middle Cerebral Artery Occlusion; Molecular; Neurons; Nuclear Translocation; Outcome; Oxygen; Pathway interactions; Patients; Poly(ADP-ribose) Polymerases; TNF Receptor-Associated Factors; TNF gene; Techniques; Testing; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; apoptosis inducing factor; clinically relevant; cytokine; deprivation; improved; in vivo; inhibitor/antagonist; intravenous administration; ischemic lesion; member; neuroimaging; neuron loss; novel therapeutic intervention; prevent; protective effect; receptor

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.

描述（由申请人提供）：肿瘤坏死因子样弱凋亡诱导剂（TWEAK）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型14（Fn 14）的细胞表面受体结合作用于应答细胞。TWEAK和Fn 14表达已在非缺血条件下在神经元中检测到，并且大脑中动脉闭塞（MCAO）或神经元培养物暴露于氧-葡萄糖剥夺（OGD）条件导致该细胞因子及其受体的表达显著增加。我们已经证明，结合TWEAK Fn 14诱导NF-？B激活和神经元细胞死亡以及MCAO后通过用可溶性Fn 14-Fc诱饵受体或Fn 14的遗传缺陷处理抑制TWEAK活性降低了缺血损伤的体积并保护了缺血半暗带的面积。在这个提议中，我们假设在脑缺血期间TWEAK和Fn 14之间的相互作用通过半胱天冬酶依赖性和非依赖性机制诱导缺血半暗带区域中的神经元细胞死亡。更具体地说，我们假设，结合TWEAK Fn 14后MCAO诱导细胞死亡的激活的“内在”和“外在”的凋亡途径，以及NF-？B-依赖性激活聚（ADP-核糖）聚合酶-1（PARP-1），伴凋亡诱导因子（AIF）核转位。此外，通过体内最先进的神经成像技术评估，MCAO后用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。