Transient senescence in tissue repair - Genetic and metabolic regulation of resistance to apoptosis during injury-induced G2-stalling in Drosophila

上皮的暴露位置使它们容易受到损伤和损伤。损伤后体内平衡的恢复依赖于对不同细胞行为的适当时空控制，如损伤诱导的凋亡、代偿性增殖和组织重塑。虽然已经确定在果蝇的想象盘中，这些过程在很大程度上是由应激反应通路JNK协调的，但我们仍然不了解这些行为的空间模式是如何被控制的，以及它们之间的反馈和串扰是如何指导组织修复过程的。我们最近证明，JNK信号在组织损伤和肿瘤中诱导细胞周期g2期的剂量依赖性延长，导致短暂的停滞或延长但可逆的细胞周期停滞。我们发现，G2的停滞诱导衰老标志，从而为解剖体内组织修复的短暂衰老程序的生理要求提供了机会。我们将利用经典的细胞生物学和遗传学方法来具体研究G2延迟如何诱导细胞周期依赖性的凋亡抗性。此外，我们将开始描述伤口愈合和组织修复的代谢程序。通过将我们在应激信号级联及其增殖和凋亡效应程序方面的核心专业知识与新兴的代谢领域相结合，我们的目标是揭示具有巨大社会影响的医疗条件的基本原理和衰老策略，例如慢性伤口愈合病理和炎症相关的衰老疾病，糖尿病和癌症。

The exposed position of epithelia makes them susceptible to injury and damage. The restoration of homeostasis after damage relies on the proper spatio-temporal control of distinct cell behaviors, such as damage-induced apoptosis, compensatory proliferation and tissue remodeling. While it is established that in Drosophila imaginal discs these processes are largely coordinated by the stress response pathway JNK, we still fail to understand how spatial patterns of these behaviors are controlled and how feed-back and crosstalk between them guides tissue repair process. We recently demonstrate that JNK signaling induces a dose-dependent extension of the G2-phase of the cell cycle in tissue damage and tumors resulting in either transient stalling or a prolonged but reversible cell cycle arrest. We found that stalling in G2 induces senescence hallmarks, thereby offering the opportunity to dissect the physiological requirements of transient senescence programs for tissue repair in vivo. We will utilize classical cell biological and genetic approaches to specifically examine how G2 stalling induces cell-cycle-dependent resistance to apoptosis. Moreover, we will begin to characterize the metabolic programs of wound healing and tissue repair. By combining our core expertise in stress signaling cascades and their proliferative and apoptotic effector programs with the emerging field of metabolism, we aim to uncover fundamental principles and senolytic strategies to address medical conditions with tremendous societal impact, such as chronic wound healing pathologies and inflammation-associated disorders of ageing, diabetes and cancer.