Mitochondrial function in the regulation of intestinal tissue regeneration and inflammation-related pathologies

肠上皮在炎症性肠病(IBD)的发病机制中起着关键作用。IBD反复发作的炎性发作损害上皮细胞，并对肠道屏障造成侮辱。损伤后的组织再生是维持/恢复屏障和免疫动态平衡的重要机制，需要对上皮的更新、增殖和(去)分化进行严格的调控。我们认为，线粒体代谢受损和上皮细胞线粒体应激信号失控(线粒体未折叠蛋白反应，MT-UPR)导致肠道组织异常反应(称为代谢损伤)。考虑到IL-22和IL-10在调节肠道屏障功能和免疫反应中的关键作用，本项目的目的是了解这些细胞因子在解决上皮细胞线粒体相关损伤中的作用，并确定导致炎症相关病理进展的破坏性机制。我们为代谢损伤(线粒体热休克蛋白60的条件性缺陷；HSP60ClpPIEC)和MT-UPR激活(酪蛋白溶解线粒体基质多肽酶的条件性缺陷；ClpPIEC)建立了我们的新型上皮细胞特异性小鼠模型。在这些模型中，将在没有IL-22信号的情况下以及在IL-10缺乏的宿主中分析组织病理和炎症的消退或进展。此外，我们应用FDA批准的研究药物二氯乙酸酯(DCA)，探索代谢转向线粒体呼吸的治疗作用。来自IBD患者(N=80)的组织样本将用于验证缓解和复发期间代谢损伤和再生组织反应的临床相关性。最后，我们打算利用小鼠和患者的肠道器官(Co)培养来确定控制代谢损伤调控电路的关键信号和机制。综上所述，我们验证了IL-22和IL-10调节上皮细胞代谢适应性的假设，从而有助于肠道代谢损伤的解决。我们认为，上皮细胞的线粒体功能是决定疾病易感性和IBD相关病理进展的关键。

The intestinal epithelium plays a key role in the pathogenesis of inflammatory bowel diseases (IBD). Recurrent inflammatory episodes in IBD damage the epithelium and represent insults to the intestinal barrier. Tissue regeneration in response to injuries is an essential mechanism to maintain/restore barrier and immune homeostasis, requiring a tight regulation of epithelial renewal, proliferation and (de)differentiation. We suggest that impaired mitochondrial metabolism and uncontrolled mitochondrial stress signaling (mitochondrial unfolded protein response, MT-UPR) in the epithelium contribute to aberrant intestinal tissue responses (referred to as metabolic injury). Considering the pivotal role of Interleukin 22 (IL-22) and IL-10 in regulating intestinal barrier function and immune responses, the aim of the present project is to understand the contribution of these cytokines to the resolution of mitochondria-related injuries in the epithelium and to identify disruptive mechanisms responsible for the progression of inflammation-related pathologies. We implement our novel epithelial cell-specific mouse models for metabolic injury (conditional deficiency of the mitochondrial heat shock protein 60; Hsp60IEC) and MT-UPR activation (conditional deficiency of the caseinolytic mitochondrial matrix peptidase; ClpPIEC). In these models, resolution or progression of tissue pathology and inflammation will be analyzed in the absence of IL-22 signaling and in the IL-10 deficient host. In addition, we apply the FDA approved investigational drug Dichloroacetate (DCA), exploring the therapeutic role of a metabolic shift towards mitochondrial respiration. Tissue samples from IBD patients (N=80) will be used to validate the clinical relevance of metabolic injury and regenerative tissue responses during remission and relapse. Finally, we intend to identify signals and mechanisms crucial for controlling regulatory circuits in response to metabolic injury using intestinal organoid (co-)cultures from mice and patients. In summary, we test the hypothesis that IL-22 and IL-10 regulate metabolic fitness of epithelial cells, and thereby contribute to the resolution of metabolic injury in the intestine. We propose that mitochondrial function of the epithelium is critically determining disease susceptibility and progression of IBD-related pathologies.