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.

项目摘要 尽管在人类克罗恩氏肠上皮细胞中发现线粒体功能障碍 疾病(CD)和溃疡性结肠炎患者，炎症性肠病(IBD)治疗 线粒体功能障碍目前是缺乏的。人们普遍认为，细胞内的线粒体池 通过被称为有丝分裂的选择性自噬来移除受损的线粒体来维持。有丝分裂可能 对肠道分泌细胞(潘氏细胞、杯状细胞、肠道内分泌细胞)的功能尤为重要 线粒体丰富，可以维持耗能的分泌功能，但这一点尚未得到证实。帕内斯 自噬缺陷可能导致的细胞功能障碍在CD患者的一部分中得到证实。然而， 线粒体应激促进炎症和潘氏细胞异常的机制是 未知。 Prohibitin 1(PHB1)是线粒体内膜(IMM)的主要组成蛋白。 调节电子传递链功能，对三磷酸腺苷的产生很重要。我们已经培育出了带有绒毛蛋白的小鼠- CRERT2诱导的肠上皮细胞特异性缺失PHB1基因(PHB1、∆、IEC) 这些小鼠表现出自发性回肠炎，并伴有线粒体功能障碍和早期潘氏细胞缺陷 在PHB1缺失后。PHB1∆IEC小鼠的Paneth细胞异常使人联想到Paneth缺陷的小鼠 细胞自噬。我们的中心假设是线粒体功能障碍与随后的抑制 肠道上皮细胞中PHB1的缺失导致吞丝分裂，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说：1.确定PHB1在线粒体功能障碍和 自发性回肠炎，2.确定PHB1在有丝分裂诱导中的作用，以及3.确定Paneth细胞 表现为线粒体功能障碍和线粒体靶向治疗是否抗炎 克罗恩回肠炎患者。长期目标是确定以线粒体为靶点 功能障碍是治疗IBD的有效策略。