Diversity Supplement to R01 Mitochondrial Dysfunction and Mitophagy in Ileitis

R01 回肠炎线粒体功能障碍和线粒体自噬的多样性补充

• 批准号: 10443329
• 负责人: ARIANNE L THEISS
• 金额: $ 4.65万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443329
• 关键词: Abnormal Cell; Autophagocytosis; Characteristics; Crohn' s disease; Crohn' s disease of the ileum; Defect; Electron Transport; Epithelial Cells; Excision; Exhibits; Functional disorder; Genes; Human; Ileitis; Inflammation; Inflammatory Bowel Diseases; Inner mitochondrial membrane; Intestines; Mitochondria; Mus; Paneth Cells; Patients; Process; Production; Proteins; Role; Secretory Cell; Stress; Testing; Therapeutic; Ulcerative Colitis; combat; experimental study; intestinal epithelium; mitochondrial dysfunction; prohibitin; targeted treatment; therapeutically effective; villin

Project Summary Although mitochondrial dysfunction is demonstrated in the intestinal epithelium of human Crohn's disease (CD) and ulcerative colitis patients, inflammatory bowel disease (IBD) therapies targeting mitochondrial dysfunction are currently lacking. It is widely appreciated that the intracellular mitochondrial pool is maintained by removal of damaged mitochondria via selective autophagy called mitophagy. Mitophagy may be especially important for the function of intestinal secretory cells (Paneth, goblet, enteroendocrine) which are mitochondria-rich to sustain energy-expending secretory functions, but this has yet to be demonstrated. Paneth cell dysfunction that can be driven by autophagy defects is demonstrated in a subset of CD patients. However, the mechanism whereby mitochondrial stress contributes to inflammation and Paneth cell abnormalities are unknown. Prohibitin 1 (PHB1) is the major component protein of the inner mitochondrial membrane (IMM) where it regulates electron transport chain function important for ATP production. We have generated mice with Villin- CreERT2 inducible intestinal epithelial cell (IEC)-specific deletion of the PHB1 gene (PHB1∆IEC) and show that these mice exhibit spontaneous ileitis preceded by mitochondrial dysfunction and Paneth cell defects early after PHB1 deletion. Paneth cell abnormalities in PHB1∆IEC mice are reminiscent of mice deficient in Paneth cell autophagy. Our central hypothesis is that mitochondrial dysfunction with subsequent inhibition of mitophagy caused by loss of PHB1 in the intestinal epithelium leads to Paneth cell dysfunction and ileitis. We will pursue 3 specific aims to test this hypothesis: 1. Define the role of PHB1 in mitochondrial dysfunction and spontaneous ileitis, 2. Determine the role of PHB1 in mitophagy induction, and 3. Define whether Paneth cells manifest mitochondrial dysfunction and whether mitochondrial-targeted therapy combats inflammation in patients with Crohn's ileitis. The long-term objective is to determine whether targeting mitochondrial dysfunction is an effective therapeutic strategy for IBD.

项目概要 尽管线粒体功能障碍在人类克罗恩病的肠上皮细胞中得到证实 疾病（CD）和溃疡性结肠炎患者，炎症性肠病（IBD）治疗针对 目前尚缺乏线粒体功能障碍。人们普遍认为细胞内线粒体库 通过选择性自噬（称为线粒体自噬）去除受损的线粒体来维持。线粒体自噬可能 对于肠道分泌细胞（潘氏细胞、杯状细胞、肠内分泌细胞）的功能尤其重要。 富含线粒体来维持能量消耗的分泌功能，但这尚未得到证实。帕内斯 在部分 CD 患者中证实了自噬缺陷可能导致细胞功能障碍。然而， 线粒体应激导致炎症和潘氏细胞异常的机制是 未知。 抑制素 1 (PHB1) 是线粒体内膜 (IMM) 的主要组成蛋白，在该蛋白中 调节对 ATP 产生很重要的电子传递链功能。我们已经用 Villin 生成了小鼠- CreERT2 诱导性肠上皮细胞 (IEC) 特异性删除 PHB1 基因 (PHB1ΔIEC) 并显示 这些小鼠早期表现出自发性回肠炎，随后出现线粒体功能障碍和潘氏细胞缺陷 PHB1删除后。 PHB1ΔIEC 小鼠的潘氏细胞异常让人想起潘氏细胞缺陷的小鼠 细胞自噬。我们的中心假设是线粒体功能障碍随后抑制 肠上皮中 PHB1 缺失引起的线粒体自噬会导致潘氏细胞功能障碍和回肠炎。我们 将追求 3 个具体目标来检验这一假设： 1. 定义 PHB1 在线粒体功能障碍中的作用， 自发性回肠炎，2. 确定 PHB1 在线粒体自噬诱导中的作用，以及 3. 确定潘氏细胞是否 明显的线粒体功能障碍以及线粒体靶向治疗是否可以对抗炎症 克罗恩回肠炎患者。长期目标是确定是否靶向线粒体 功能障碍是 IBD 的有效治疗策略。