Mitochondrial Dysfunction and Mitophagy in Ileitis

回肠炎中的线粒体功能障碍和线粒体自噬

基本信息

批准号：
10450818
负责人：
ARIANNE L THEISS
金额：
$ 34.93万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450818
关键词：
Abnormal Cell Address Autophagocytosis Biopsy Cells Characteristics Crohn&apos s disease Crohn&apos s disease of the ileum Data Defect Development Electron Transport Enteroendocrine Cell Epithelial Cells Excision Exhibits Functional disorder Generations Genes Goals Goblet Cells Homeostasis Human Ileitis In Vitro Inflammation Inflammatory Bowel Diseases Inner mitochondrial membrane Intestines Killer Cells Link Maintenance Mitochondria Mitochondrial Membrane Protein Mucous Membrane Mus Outer Mitochondrial Membrane Oxidative Phosphorylation Paneth Cells Patients Play Process Production Proteins Reactive Oxygen Species Role Secretory Cell Stress Testing Therapeutic Toxic effect Ulcerative Colitis combat experimental study gut inflammation in vivo intestinal epithelium intestinal homeostasis mitochondrial dysfunction novel novel therapeutic intervention patient subsets prevent prohibitin side effect targeted treatment therapeutically effective villin

项目摘要

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.

项目摘要在人类克罗恩病的肠上皮（CD）中证明了Althooth Mitchondrial功能障碍和溃疡性结肠炎患者，针对线粒体功能障碍的炎性肠病（IBD）疗法目前缺乏。通过选择性自噬被称为线粒体的线粒体受损的线粒体。肠分泌细胞（Paneth，Goblet，肠内分泌）的功能，富含线粒体。维持能源膨胀的分泌功能，但这尚待证明。可以在CD患者的子集中证明自噬缺陷线粒体应激会导致炎症，而Paneth细胞异常尚不清楚。禁止素1（PHB1）是内部线粒体膜（IMM）的主要成分蛋白调节电子运输链对ATP的功能很重要。 Creert2诱导肠道细胞（IEC） - PHB1基因（PHB1ΔIEC）的特异性缺失，并表明这一点这些小鼠表现出自发性回肠炎，先于线粒体功能障碍，并早日paneth细胞缺陷 PHB1划定后。自噬，我们的中心假设是线粒体功能障碍由肠上皮中的PHB1丢失导致Paneth细胞功能障碍和回肠炎。特定的目的是检验以下假设：1。定义PHB1在Mitchondrial功能障碍和自发性中的作用回肠炎，2。确定PHB1在线粒体指示中的作用，3。定义Paneth细胞是否表现出来线粒体功能障碍以及线粒体靶向治疗是否会打击患者的炎症克罗恩的回肠炎。 IBD的有效治疗策略。