TWEAK-Induced Ischemic Neuronal Death

TWEAK 诱导的缺血性神经元死亡

• 批准号: 7727178
• 负责人: Manuel Salvador Yepes
• 金额: $ 34.89万
• 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/7727178
• 关键词: Acute; Adaptor Signaling Protein; Animal Model; Apoptosis Promoter; Apoptotic; Area; Arts; Binding; Caspase; Cell Death; Cell Death Inhibition; Cell Surface Receptors; Cells; Cerebral Ischemia; Cessation of life; Clinical; Fibroblast Growth Factor; Genetic; Glucose; 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; Techniques; Testing; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; 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; public health relevance; 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. 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.

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 (Fn14) 的细胞表面受体结合而作用于应答细胞。在非缺血条件下，神经元中已检测到 TWEAK 和 Fn14 的表达，大脑中动脉闭塞 (MCAO) 或神经元培养物暴露于氧糖剥夺 (OGD) 条件下会导致该细胞因子及其受体的表达显着增加。我们已经证明，TWEAK 与 Fn14 的结合诱导 NF-κB 激活和神经元细胞死亡，并且通过用可溶性 Fn14-Fc 诱饵受体治疗或 Fn14 遗传缺陷来抑制 MCAO 后的 TWEAK 活性，可减少缺血性病变的体积并保护缺血半影区域。在本提议中，我们假设脑缺血期间 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 MCAO 后 TWEAK 与 Fn14 的结合通过激活“内在”和“外在”凋亡途径以及通过 NF-κB 依赖性激活聚（ADP-核糖）聚合酶-1（PARP-1）以及凋亡诱导因子（AIF）的核转位来诱导细胞死亡。此外，根据体内最先进的神经影像技术评估，MCAO后使用TWEAK活性抑制剂治疗可减少脑缺血引起的神经元死亡，并改善缺血组织的命运。这些临床相关研究可能会产生一种新的治疗方法来预防缺血性中风患者的神经元细胞死亡。公共卫生相关性：缺血性中风发作后早期，细胞因子 TWEAK 及其受体 Fn14 的表达增加。 TWEAK 与 Fn14 的结合会诱导神经元死亡。本申请重点研究 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中风期间神经元死亡的潜在治疗策略。