Investigating the role of mitochondria in Eosinophilic Esophagitis pathogenesis.

项目摘要 嗜酸性食管炎(EoE)是一种慢性食物过敏，其病理生物学尚不完全。 明白了。编码线粒体蛋白DHTKD1的核基因的破坏性变体已经被 在EoE患者中发现，表明线粒体在EoE病理生物学中可能发挥作用。我们之前已经 报道IL-13诱导自噬通量作为一种细胞保护机制暴露的食道上皮 与EoE相关的炎性刺激。为了扩展这些研究，我们评估了IL-13对 线粒体，一个公认的自噬的细胞靶点。出乎意料的是，我们发现 经IL-13处理的食道角质形成细胞线粒体减少，而不是假设的减少。在此期间 在我的实验室里，杰克逊女士(目前的多样性补充剂候选人)发现，在与EoE相关的 细胞因子IL-13独特地增加了食道角质形成细胞的线粒体。她进一步证明了 线粒体转录因子TFAM的敲除部分恢复了IL-1鳞状细胞的分化 13-治疗后的食道器官。基于这些发现，我们假设IL-13介导的改变 线粒体生物学在EoE鳞状细胞分化受损中起重要作用。这些研究将利用 在Parent R01期间开发的实验平台和方法，以探索这一创新 假设。目前提议的具体目标是：目标1.通过以下方式确定分子机制 IL-13诱导的食道角质形成细胞线粒体含量增加；和目的2.阐明 线粒体在EoE发病机制中的功能作用综上所述，这些研究将提供新的见解 探讨线粒体在EoE发病机制中的作用。上皮分化的恢复可能会促进 EoE患者的上皮愈合和屏障功能，从而限制进一步的抗原提呈。因此， 这项研究的发现可能会对EoE产生翻译影响。拟议的研究将进一步提供 杰克逊女士在发展新的概念和技术专长时获得了极好的培训机会 与线粒体生物学相关，并制定了她的F31建议。

Project Summary Eosinophilic Esophagitis (EoE) is a chronic type of food allergy whose pathobiology remains incompletely understood. Damaging variants in the nuclear gene encoding the mitochondrial protein DHTKD1 have been identified in EoE patients, indicating a potential role for mitochondria in EoE pathobiology. We have previously reported that IL-13 induces autophagy flux as a cytoprotective mechanism in esophageal epithelium exposed to EoE-relevant inflammatory stimuli. To extend these studies, we evaluated the impact of IL-13 upon mitochondria, a well-established cellular target of autophagy. Unexpectedly, we found an increase in mitochondria in esophageal keratinocytes treated with IL-13 rather than the hypothesized decrease. During her rotation in my lab, Ms. Jackson (the current diversity supplement candidate) found that among EoE-relevant cytokines IL-13 uniquely increased mitochondria in esophageal keratinocytes. She further demonstrated that knockdown of the mitochondrial transcription factor TFAM partially restored squamous cell differentiation in IL- 13-treated esophageal organoids. Based upon these findings, we hypothesize that IL-13-mediated alterations in mitochondrial biology contribute to impaired squamous cell differentiation in EoE. These studies will utilize the experimental platforms and approaches developed during the parent R01 to explore this innovative hypothesis. The Specific Aims of the current proposal are: Aim 1. To define the molecular mechanisms through which IL-13 induces increased mitochondrial content in esophageal keratinocytes; and Aim 2. To elucidate the functional role of mitochondria in EoE pathogenesis. Taken together, these studies will provide novel insight into the role of mitochondria in EoE pathogenesis. Restoration of epithelial differentiation may promote epithelial healing and barrier function in EoE patients, thereby limiting further antigen presentation. Thus, findings from this study have potential for translational impact in EoE. The proposed studies will further provide excellent training opportunities for Ms. Jackson as she develops novel conceptual and technical expertise related to mitochondrial biology and formulated her F31 proposal.