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

上皮细胞暴露的位置使其容易受到损伤和破坏。损伤后动态平衡的恢复依赖于对不同的细胞行为的适当的时空控制，如损伤诱导的细胞凋亡、代偿性增殖和组织重塑。虽然在果蝇的想象盘中，这些过程在很大程度上是由应激反应途径JNK协调的，但我们仍然不能理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如何指导组织修复过程。我们最近证明，在组织损伤和肿瘤中，JNK信号诱导细胞周期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中的停滞会诱导衰老标志，从而为剖析体内组织修复的瞬时衰老程序的生理需求提供了机会。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停滞是如何诱导细胞周期依赖性的细胞凋亡抵抗的。此外，我们将开始描述伤口愈合和组织修复的代谢程序。通过将我们在压力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新陈代谢领域相结合，我们旨在揭示基本原则和分解衰老的策略，以应对具有巨大社会影响的医疗条件，例如慢性伤口愈合病理和与炎症相关的衰老、糖尿病和癌症疾病。

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.