Investigating the role of mitochondria in Eosinophilic Esophagitis pathogenesis.

项目概要 嗜酸性粒细胞性食管炎 (EoE) 是一种慢性食物过敏，其病理学仍不完全清楚 明白了。编码线粒体蛋白 DHTKD1 的核基因中的破坏性变异已被证实 在 EoE 患者中发现，表明线粒体在 EoE 病理学中的潜在作用。我们之前有过 据报道，IL-13 诱导自噬流作为暴露的食管上皮的细胞保护机制 EoE 相关的炎症刺激。为了扩展这些研究，我们评估了 IL-13 对 线粒体，一个公认的自噬细胞靶点。没想到我们发现增加了 用 IL-13 处理的食管角质形成细胞中的线粒体，而不是假设的减少。在她期间 在我的实验室轮换中，Jackson 女士（目前的多样性补充候选人）发现，在与 EoE 相关的 细胞因子 IL-13 独特地增加了食管角质形成细胞中的线粒体。她进一步证明 线粒体转录因子 TFAM 的敲低可部分恢复 IL- 中的鳞状细胞分化 13 处理过的食管类器官。基于这些发现，我们假设 IL-13 介导的改变 线粒体生物学中的线粒体生物学功能导致 EoE 中鳞状细胞分化受损。这些研究将利用 在母 R01 期间开发的实验平台和方法，以探索这一创新 假设。当前提案的具体目标是： 目标 1. 通过以下方式定义分子机制： IL-13 诱导食管角质形成细胞中线粒体含量增加；目标 2. 阐明 线粒体在 EoE 发病机制中的功能作用。总而言之，这些研究将提供新颖的见解 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呈递。因此， 这项研究的结果有可能对 EoE 产生转化影响。拟议的研究将进一步提供 为杰克逊女士提供极好的培训机会，帮助她发展新颖的概念和技术专业知识 与线粒体生物学相关并制定了她的 F31 提案。

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.