The Role of Crypt Fissioning in IBD Ulcer Healing

隐窝分裂在 IBD 溃疡愈合中的作用

• 批准号: 10358590
• 负责人: Terrence A. Barrett
• 金额: $ 66.28万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-24 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358590
• 关键词: Biochemical; Biogenesis; Biopsy; Childhood; Chronic; Clinical; Clinical Data; Clinical Research; Colitis; Crohn' s disease; Data; Disease; Disease Outcome; Disease remission; Drops; Epithelial Cells; Failure; Gene Expression; Generations; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; In Vitro; Inflammation; Inflammatory Bowel Diseases; Injury; Intestines; Investigation; Knockout Mice; Leukocyte L1 Antigen Complex; Maintenance; Measures; Mitochondria; Modeling; Monoclonal Antibodies; Mucositis; Mucous Membrane; Mus; Operative Surgical Procedures; Outcome; Oxidation-Reduction; PTEN gene; Pathogenesis; Patients; Phosphatidylinositols; Phosphotransferases; Principal Investigator; Procedures; Refractory; Respiration; Respiratory Chain; Role; Signal Transduction; Site; TNF gene; Tattooing; Testing; Treatment Efficacy; Ulcer; Ulcerative Colitis; Visualization; WNT Signaling Pathway; Work; base; beta catenin; chronic ulcer; clinical phenotype; crypt cell; dextran sulfate sodium induced colitis; drug development; experience; healing; infliximab; intestinal epithelium; new therapeutic target; novel; novel strategies; prevent; programs; prospective; repaired; response; single-cell RNA sequencing; stem cells; therapeutic biomarker; therapeutic target; transcriptomics

Program Director/Principal Investigator (Barrett, Terrence, A): The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data that demonstrate it to be a predictor of remission1. Thus, ulcer healing predicts the capacity for therapies to prevent unwanted clinical sequelae (i.e. surgery). 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)2. These findings were supported by Kugathasan et al who found that increased expression of mitochondrial respiratory chain genes predicted favorable (B1 protected) Crohn’s disease (CD) outcomes3. 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 with ROS generation. We posit that chronic mucosal inflammation suppresses mitochondrial respiration needed for crypt fissioning (in ulcer healing) in IBD. This hypothesis will be tested in the following studies: Aim 1. Determine the impact of mitochondrial respiration for mucosal healing. These studies benefit from strikingly novel Prelim. Data using VilCre/mTmG/TFAMfl/fl mice where mitochondrial respiration was shown to be required for crypt fissioning in ulcer healing. In Aim 2 we will determine the requirement of mitochondrial- derived ROS in IEC crypt division using primary human colonoids. Aim 3 studies will determine the impact of chronic inflammation on ulcer healing in patients. IEC transcriptomics from ulcer edges from CD and ulcerative colitis will be compared to normal ulcer healing. Normal ulcer healing will be interrogated using a novel biopsy of a biopsy (Bx/Bx) approach (IEC will be isolated from Bx/Bx sites 4-6day after initial biopsies). ScRNAseq results have already shown that mitochondrial biogenesis (PGC1) increases in Bx/Bx ulcers whereas levels drop in IBD IEC. In summary: Studies will investigate the cause of non-healing ulceration in IBD by interrogating novel murine, human and in vitro colonoid culture models of determining the impact of suppressed mitochondrial respiration on IEC responses (crypt fissioning). The studies will test the notion that chronic mucosal inflammation (as in IBD) suppresses mitochondrial respiration which impedes ROS-induced PI3K signaling and crypt fissioning. Our goal is to identify therapeutic targets to allow for enhanced mitochondrial respiration to aide mucosal repair in IBD. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

项目主任/首席研究员（巴雷特，特伦斯，A）：