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

组织修复中的短暂衰老——果蝇损伤诱导的 G2 停滞过程中抗凋亡的遗传和代谢调节

• 批准号: 445566635
• 负责人: Professorin Dr. Anne-Kathrin Classen
• 金额: --
• 依托单位: CIBSS Centre for Integrative Biological Signalling Studies
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/445566635?language=en
• 关键词: Transient; senescence; tissue; repair; Genetic

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.

上皮细胞暴露的位置使它们容易受到伤害和损害。损伤后稳态的恢复依赖于对不同细胞行为的适当时空控制，例如损伤诱导的细胞凋亡、代偿性增殖和组织重塑。虽然已经确定，在果蝇成虫盘中，这些过程在很大程度上是由应激反应通​​路 JNK 协调的，但我们仍然无法理解这些行为的空间模式是如何控制的，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，JNK 信号传导可诱导组织损伤和肿瘤中细胞周期 G2 期的剂量依赖性延长，从而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 期的停滞会诱导衰老标志，从而提供了剖析体内组织修复短暂衰老程序的生理要求的机会。我们将利用经典的细胞生物学和遗传学方法来专门研究 G2 停滞如何诱导细胞周期依赖性细胞凋亡抵抗。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，我们的目标是揭示基本原理和衰老策略，以解决具有巨大社会影响的医疗状况，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。