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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：
10219235
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219235
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 in vivo inflammatory disease of the intestine 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.

项目总结