Modulation of mitochondrial respiration to treat colitis

调节线粒体呼吸来治疗结肠炎

• 批准号: 10560494
• 负责人: Terrence A. Barrett
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560494
• 关键词: 3-Dimensional; 3-nitrotyrosine; Acceleration; Antioxidants; Auranofin; Bioenergetics; Biogenesis; Biopsy; Cell Survival; Cells; Childhood; Chronic; Clinical; Clinical Data; Colitis; Colon; Crohn' s disease; Data; Disease; Disease Outcome; Disease remission; Distant; Electron Transport; Epithelial Cells; Event; Failure; Gene Expression; Genes; Glutathione; Goals; Gold; Gold Compounds; Healthcare Systems; Human; Hydrogen Peroxide; Immunosuppression; In Vitro; Incubated; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Messenger RNA; Mitochondria; Modeling; Morbidity - disease rate; Mucositis; Mucous Membrane; Mus; Oral; Organ; Organoids; Outcome; Oxidative Phosphorylation; Oxidative Stress; Oxygen Consumption; PPAR gamma; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Production; Progress Reports; Proteins; Reactive Oxygen Species; Refractory; Research; Respiration; Respiratory Chain; Rheumatoid Arthritis; Risk; Role; SOD2 gene; Secondary to; Signal Induction; Signal Transduction; Small Intestines; Superoxide Dismutase; TNF gene; Testing; Therapeutic; Therapeutic Effect; Therapeutic Studies; Tissues; Toxicology; Ulcer; Ulcerative Colitis; Veterans; Work; antioxidant enzyme; catalase; chronic ulcer; cytokine; dextran sulfate sodium induced colitis; enzyme activity; healing; improved; in vivo; innovation; intestinal crypt; intestinal epithelium; mtTF1 transcription factor; murine colitis; novel; novel therapeutics; nuclear factor-erythroid 2; oxidant stress; preclinical study; prospective; protein expression; repaired; response; restoration; synergism; uptake

The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data that demonstrate it to be a predictor of remission. Unfortunately, many IBD patients remain refractory or lose responsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies show that reduced mitochondrial gene expression predict unfavorable outcomes in ulcerative colitis (UC). Consistently, increased expression of mitochondrial respiratory chain genes has been shown to predict favorable Crohn’s disease (CD) outcomes. Based on these results and our own data, we hypothesize that a critical driver of chronic ulceration in IBD is the failure of intestinal epithelial cells (IEC) to increase mitochondrial respiration. In studies leading up to this submission we found that mitochondrial deficiency caused poor ulcer healing due to inadequate crypt fissioning occurring at ulcer edges (Progress Report). These findings led us to develop a novel gold (Au)- based drug based on the current safe and effective gold therapy for Rheumatoid arthritis (Auranofin). This new drug, AuPhos, localizes to mitochondria where it increases mitochondrial respiration and mitochondrial reactive oxygen species (mtROS) production. Induction of low levels of “endogenous” mtROS are known to promote healthy adaptive responses in cells including anti-oxidant enzyme activities (Background). In preliminary studies, we found that oral AuPhos 1) enhances mucosal repair in DSS colitis, 2) increases IEC mitochondrial oxygen consumption rate (OCR) and oxidative phosphorylation (OXPHOS), 3) mtROS and H2O2 production in IEC as well as 4) phosphoinositides-3 kinase (PI3K) and nuclear factor erythroid 2-related factor (Nrf2) signaling with 5) improved expression of proteins that induce mitochondrial biogenesis [peroxisome proliferator activated receptor-γ coactivator 1 alpha (PGC1α) and transcription factor A, mitochondrial (TFAM). Studies proposed in Aim 1 interrogate mitochondrial function under baseline conditions to allow assessment of AuPhos-induced changes in mitochondrial mass, activity (mtROS) and OCR, ATP turnover, electron transport chain (ETC) activity, induction of adaptive responses [anti-oxidant catalase, MnSOD (superoxide dismutase) and glutathione (reduced/oxidized)] as well as assess changes in tissue oxidant stress (4HNE, protein carbonylation, nitrotyrosine IHC). Aim 2 will build upon these studies by evaluating AuPhos effects in TNF-stimulated small bowel (SB) and colonic organoids from veterans (normal and IBD). Studies in 3D organoids will allow for mechanistic testing of AuPhos-induced crypt budding and IEC gene expression. Results of Aim 2 will instruct studies in Aim 3A that study therapeutic effects of AuPhos on IEC gene expression and crypt fissioning that heal ulcers in DSS colitis. In Aim 3B, scRNAseq analysis of human biopsies incubated with AuPhos will allow us to examine induction of mitochondrial gene expression in discrete IEC clusters. Proposed studies are driven by a novel hypothesis that restoration of IEC mitochondrial respiration is a key step in mucosal healing. Together, these “preclinical” studies with a VA-sponsored new drug (AuPhos) have the potential of transitioning this agent to the therapy of IBD in veterans.

粘膜愈合在炎症性肠病（IBD）中的重要性来源于临床数据