Telomere Dysfunction as an Initiator of Inflammation: Clues to an Age-Old Mystery.

Journal of inflammatory bowel diseases & disorders Pub Date : 2021-01-01 Epub Date: 2021-02-17
Deepavali Chakravarti, Ronald A DePinho
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Abstract

Inflammatory Bowel Disease (IBD) is a challenging medical condition that is driven by various genetic and environmental factors. Therapeutic opportunities for this disease remain limited due to the lack of in-depth understanding of the pathogenetic mechanisms and actionable targets driving the disease. Analysis of telomere dysfunctional mice and patients with genetic defects in telomere maintenance unexpectedly revealed phenotypes mirroring those observed in IBD. Molecular characterization of this model identified a pathway driven by telomere DNA damage-mediated activation of the ATM/cABL/YAP1 pathway, which directly regulates genes central to IBD pathogenesis and amenable to therapeutic intervention. This review summarizes the evidence correlating telomere dysfunction with IBD and colitis-associated cancer and proposes therapeutic opportunities for such inflammatory conditions targeting this newly identified pathway.

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端粒功能障碍是炎症的发起者:一个古老谜团的线索。
炎症性肠病(IBD)是一种具有挑战性的疾病,由各种遗传和环境因素驱动。由于缺乏对该病发病机制和可操作靶点的深入了解,该病的治疗机会仍然有限。对端粒功能失调小鼠和端粒维持遗传缺陷患者的分析意外地揭示了与IBD中观察到的表型相一致的表型。该模型的分子表征确定了一条由端粒DNA损伤介导的ATM/cABL/YAP1通路激活驱动的通路,该通路直接调控IBD发病机制的核心基因,并可接受治疗干预。本综述总结了端粒功能障碍与IBD和结肠炎相关癌症相关的证据,并提出了针对这一新发现的途径治疗此类炎症的机会。
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