Cellular and molecular mechanisms of tumor necrosis factor receptor 2 mediated neuroprotection in spinal cord injury

肿瘤坏死因子是一种多功能细胞信号蛋白，在神经退行性疾病中具有双重作用。通过肿瘤坏死因子受体1(TNFR1)介导的信号促进炎症和组织退变，而通过TNFR2介导的信号有助于神经保护和组织再生。由于TNFR2的这种重要的再生作用，特异性激活TNFR2的分子可以促进神经退行性疾病的恢复。为了继续我之前的工作，我开发了第一个临床适用的TNFR2激动剂，现在我想研究这种分子在创伤性脊髓损伤中的治疗效果。在这些研究中，治疗结果将通过行为和组织学分析以及电生理评估进行监测。特别是，通过使用转基因小鼠，在特定的神经胶质细胞中可以诱导TNFR2被敲除，将有可能确定通过TNFR2信号介导的抗炎和再生效应的细胞和分子机制。脊髓损伤模型的预期研究将为TNFR2激动剂治疗神经退行性疾病的可能临床试验铺平道路，并可能导致创伤性脊髓损伤治疗的发展。

Tumor necrosis factor (TNF) is a multifunctional cell signaling protein that plays a dual role in neurodegenerative diseases. Signaling mediated via TNF receptor 1 (TNFR1) promotes inflammation and tissue degeneration, whereas signaling via TNFR2 contributes to neuroprotection and tissue regeneration. Due to this important regenerative role of TNFR2, molecules that specifically activate TNFR2 could promote recovery in neurodegenerative diseases. To continue my previous work, where I developed the first clinically applicable TNFR2 agonist, I now want to investigate the therapeutic efficacy of this molecule in traumatic spinal cord injury. In these studies, the therapeutic outcome will be monitored by behavioral and histological analyses as well as electrophysiological assessments. In particular, by using transgenic mice, where TNFR2 can be inducible knocked-out in specific glial cells, it will be possible to identify cellular and molecular mechanism underlying the anti-inflammatory and regenerative effects mediated via TNFR2 signaling. The intended studies in the spinal cord injury model will pave the way for possible clinical trials with TNFR2 agonists in neurodegenerative diseases and may lead to the development of a therapy for traumatic spinal cord injury.