Role of senescent cells in pathogenesis of contusive spinal cord injury

脊髓损伤(SCI)后，最初的机械损伤之后是继发性损伤，加重 组织破坏和功能缺陷。在胸部挫伤中，脑白质损害，进展为 损伤后几周，是运动功能障碍的关键解剖学决定因素。几乎没有什么目标是 确定谁的手法减少了脊髓损伤相关的继发性损伤，治疗窗口为12-24小时。 虽然在脊髓损伤啮齿动物中观察到了运动功能的恢复，但通常是不完全的。复苏的限制包括 神经元和少突胶质细胞丢失，炎症反应延长，血管功能障碍，缺乏效率 再生，和/或有限的突触可塑性。打破运动恢复的天花板 啮齿动物仍然是一个重大挑战。积累DNA损伤的增殖细胞可能会经历细胞 衰老。细胞周期蛋白依赖性激酶(CDK)抑制剂p21和p16的衰老诱导 触发永久退出细胞周期。衰老相关分泌表型(SASP)包括 分泌多种细胞毒性促炎介质。消除衰老细胞(衰老)的效果提高 许多年龄相关的病理改变和减轻小鼠额颞叶模型的神经退行性变 痴呆症或β-淀粉样变性。在这些病例中，改善的结果与消除衰老有关。 小胶质细胞/星形胶质细胞或少突胶质前体细胞(OPC)。随着这些神经胶质细胞的增殖 中枢神经系统损伤，它们的衰老很可能是创伤诱导的胶质细胞增多症的副产品。我们的初步数据显示 T9挫伤脊髓损伤后dpi 3和42的细胞衰老标志物表达增加。因此，通过 促进神经炎症和组织疤痕形成，衰老的细胞可能会增加白质丢失和 挫伤脊髓损伤后神经修复/神经可塑性受损。我们假设衰老的积聚 脊髓损伤后的细胞有助于进行性白质丢失，并降低运动功能的恢复。在AIM 1我们将确定脊髓损伤后衰老细胞的特性和时空分布。 老鼠。在目标2中，我们将测试药物(2a)或药物遗传(2b)对白质的影响。 中度T9挫伤后的保留和后肢运动功能。感官分解的影响将是 通过分析衰老标志物、神经炎症、反应性胶质细胞增生症、细胞凋亡、白质进行评估 节制，以及后肢运动。这些研究将最终评估脊髓损伤的致病意义。 伴随的细胞衰老。由于抗衰老药物已经用于其他疾病的临床试验，这些 研究可能定义一种新的、易于翻译的治疗急性和慢性脊髓损伤的治疗方法。 诱发的病理学。尽管有人提出，机体衰老可能会改变脊髓损伤的预后，但这一点 应用的重点是一个完全不同的问题，这是以前没有解决的：致病作用 损伤导致的细胞衰老。

After spinal cord injury (SCI), initial mechanical damage is followed by a secondary injury that exacerbates tissue destruction and functional deficits. In contusive thoracic SCI, white matter damage, which progresses for weeks post-injury, is the critical anatomical determinant of locomotor dysfunction. Few targets have been identified whose manipulation reduces SCI-associated secondary injury with a therapeutic window of <12-24 h. Although locomotor recovery is observed in SCI rodents, it is usually incomplete. The limits to recovery involve neuron and oligodendrocyte loss, prolonged inflammatory responses, vascular dysfunction, lack of efficient regeneration, and/or a finite capacity of synaptic plasticity. Breaking the ceiling of locomotor recovery in rodents remains a major challenge. Proliferating cells that accumulate DNA damage may undergo cellular senescence. Senescence-associated induction of the cyclin-dependent kinases (CDK) inhibitors p21 and p16 triggers permanent exit from the cell cycle. The senescence-associated secretory phenotype (SASP) involves secretion of multiple cytotoxic pro-inflammatory mediators. Elimination of senescent cells (senolysis) improves many age-dependent pathologies and reduces neurodegeneration in mouse models of fronto-temporal dementia or β-amyloidosis. In those cases, improved outcomes were associated with elimination of senescent microglia/astrocytes or oligodendrocyte precursor cells (OPCs). As those glial cells proliferate in response to CNS injury, their senescence is a likely by-product of trauma-induced gliosis. Our preliminary data reveal increased expression of cellular senescence markers at dpi 3 and 42 following T9 contusive SCI. Hence, by promoting neuroinflammation and tissue scarring, senescent cells may increase white matter loss and compromise neurorepair/neuroplasticity after contusive SCI. We hypothesize that accumulation of senescent cells after SCI contributes to progressive white matter loss and reduces recovery of locomotor function. In aim 1 we will determine the identity and spatio-temporal distribution of senescent cells in the spinal cord of SCI mice. In aim 2 we will test effects of pharmacological (2a) or pharmacogenetic (2b) senolysis on white matter sparing and hindlimb locomotor function after moderate T9 contusive SCI. Effects of senolysis will be evaluated by analyzing senescence markers, neuroinflammation, reactive gliosis, apoptosis, white matter sparing, and hindlimb locomotion. These studies will conclusively evaluate the pathogenic significance of SCI- associated cellular senescence. As senolytic drugs are already in use in clinical trials for other diseases, these studies may define a novel and readily translatable therapeutic treatment for both acute and chronic SCI- induced pathologies. Although it has been proposed that organismal aging may modify outcome of SCI, this application is focused on an entirely distinct issue that has not been previously addressed: the pathogenic role of injury-induced cellular senescence.