A pilot study to define maintained alterations in mitochondrial DNA of eosinophilic esophagitis patients that may be exploited clinically

一项初步研究，旨在确定嗜酸性食管炎患者线粒体 DNA 的持续改变，并可在临床上加以利用

• 批准号: 10308684
• 负责人: Kelly A Whelan
• 金额: $ 7.93万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-30 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308684
• 关键词: Abdominal Pain; Address; Age; Allergic; Antioxidants; Area; Biological Markers; Biology; Biopsy; Biopsy Specimen; Biotin; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Coenzyme Q10; Complement; Complementarity Determining Regions; DNA; DNA Damage; DNA Packaging; DNA Repair; DNA Sequence Alteration; DNA sequencing; Data; Deglutition Disorders; Disease; Disease remission; Electron Transport; Enzymes; Eosinophilic Esophagitis; Epithelial; Esophageal Diseases; Esophageal mucous membrane; Esophagus; Ethnic Origin; Exposure to; FDA approved; Food; Food Hypersensitivity; Foundations; Frequencies; Functional disorder; Future; Gastroesophageal reflux disease; Genes; Goals; Immune; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Knowledge; Longitudinal cohort; Mediating; Micronutrients; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Mus; Mutation; Nuclear; Organoids; Patients; Pilot Projects; Pre-Clinical Model; Prognosis; Quantitative Reverse Transcriptase PCR; Race; Reactive Oxygen Species; Recurrence; Respiratory Chain; Role; Sampling; Serum; Signal Transduction; Single Nucleotide Polymorphism; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; United States National Institutes of Health; Variant; Zinc; antioxidant therapy; clinical care; cohort; enzyme replacement therapy; eosinophil; food antigen; functional restoration; gene therapy; genome editing; human disease; human subject; improved; individual patient; inflammatory milieu; insertion/deletion mutation; keratinocyte; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; novel strategies; novel therapeutic intervention; responders and non-responders; response; sex; targeted treatment; translational medicine; translational potential; treatment response

Project Summary Eosinophilic Esophagitis (EoE) is a chronic, food antigen-mediated disease characterized by eosinophil-rich esophageal inflammation and symptoms such as abdominal pain, dysphagia and food impaction. A recent study identified damaging variants in the gene encoding the mitochondrial protein DHTKD1 in EoE patients. Although this indicates a potential role for mitochondria in EoE pathobiology, it remains unclear whether alterations in mitochondrial DNA are present in EoE and may be leveraged to improve clinical care of EoE patients. Indeed, mitochondria house reactive oxygen species (ROS)-producing electron transport chain components and have less sophisticated DNA repair mechanisms as compared to nuclear DNA, making mitochondria DNA highly susceptible to ROS-induced genetic alterations. This information in concert with our preliminary findings indicating (i) that there is an increase in mitochondria in esophageal epithelium of patients with active EoE that fails to normalize in inactive EoE patients; and (ii) mitochondrial dysfunction is induced in esophageal keratinocytes upon exposure to the EoE inflammatory milieu, led us to hypothesize that alterations in mitochondrial DNA may be acquired in esophageal mucosa of patients with Active EoE and maintained in a subset of Inactive patients in clinical disease remission. To test this hypothesis, we will pursue the following specific aims: Aim 1: Perform mitochondrial DNA sequencing in biopsy specimens from a cross-sectional cohort of human subjects comprising Normal controls as well as patients with Active and Inactive EoE. Gastroesophageal reflux disease patients will be evaluated to determine whether identified mitochondrial DNA alterations are specific to EoE. Aim 2: Perform mitochondrial DNA sequencing in biopsy specimens from a longitudinal cohort of human subjects comprising patients with tissues available at the time of both Active EoE and Inactive EoE and classified as therapeutic responders or non-responders. This study will (i) determine if mitochondrial DNA damage is a feature of EoE, both Active and Inactive; (ii) assess the relationship between mitochondrial DNA mutational burden and therapeutic response in EoE; and (iii) identify recurrent mitochondrial mutations that may be targeted therapeutically in EoE. Examples of potential mitochondria- targeted therapies for EoE include, delivery of antioxidant compounds (e.g. Coenzyme Q10) or micronutrients (e.g. Zinc, Biotin) to improve mitochondrial function, enzyme replacement therapy to restore the function of faulty enzymes encoded by mitochondrial DNA, and Adenoviral or CRISPR-mediated editing of the mitochondrial genome. Data generated in this study will provide the foundation for a future NIH R01 proposal that will delineate the functional significance of mitochondrial DNA alterations in EoE pathobiology and also evaluate therapeutic strategies related to mitochondrial dysfunction using preclinical models, including primary epithelial cultures, patient-derived esophageal organoids, and murine EoE models.

项目总结