Investigating the role of mitochondria in Eosinophilic Esophagitis pathogenesis.

研究线粒体在嗜酸性食管炎发病机制中的作用。

• 批准号: 10516513
• 负责人: Kelly A Whelan
• 金额: $ 1.15万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-04 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516513
• 关键词: Affect; Antigen Presentation; Area; Autophagocytosis; Biology; Cell Differentiation process; Chronic; Disease; Eosinophilic Esophagitis; Epithelial; Esophagus; Exposure to; Food Hypersensitivity; Functional disorder; Genes; Goals; Impairment; Inflammatory; Interleukin-13; Mediating; Mitochondria; Mitochondrial Proteins; Molecular; Nuclear; Organoids; Parents; Pathogenesis; Patient Care; Patients; Reporting; Role; Rotation; Signal Transduction; Squamous Cell; Stimulus; Technical Expertise; Tissues; Variant; base; cellular targeting; clinical care; cytokine; healing; human disease; improved; innovation; insight; keratinocyte; knock-down; novel; novel strategies; restoration; training opportunity; transcription factor; translational impact; translational medicine; translational potential

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.

项目摘要 嗜酸性食管炎（EoE）是一种慢性食物过敏，其病理机制尚不完全清楚 明白编码线粒体蛋白DHTKD 1的核基因中的破坏性变体已经被发现， 在Eoe患者中发现了这一点，表明线粒体在Eoe病理生物学中的潜在作用。我们先前已经 报道，IL-13诱导自噬通量作为暴露于IL-13的食管上皮细胞的细胞保护机制， 与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，一个公认的细胞自噬目标。出乎意料的是，我们发现 用IL-13处理的食管角化细胞中的线粒体减少，而不是假设的减少。期间 杰克逊女士（目前的多样性补充候选人）发现，在EoE相关的 细胞因子IL-13独特地增加了食管角化细胞中的线粒体。她进一步证明， 线粒体转录因子TFAM的敲低部分恢复了IL-10诱导的鳞状细胞分化。 13-治疗的食管类器官。基于这些发现，我们假设IL-13介导的改变 在线粒体生物学中，EoE鳞状细胞分化受损。这些研究将利用 在R 01期间开发的实验平台和方法，以探索这一创新 假说.本提案的具体目标是：目标1。为了确定分子机制， 其中IL-13诱导食管角化细胞中线粒体含量增加;和Aim 2.阐明本 线粒体在EoE发病机制中的功能作用。综合起来，这些研究将提供新的见解， 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，在本发明中， 这项研究的发现有可能对EoE产生翻译影响。拟议的研究将进一步提供 为杰克逊女士提供了极好的培训机会，因为她开发了新的概念和技术专长 与线粒体生物学有关，并制定了她的F31提案。