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：
10557967
负责人：
ARIANNE L THEISS
金额：
$ 8.83万
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/10557967
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.

项目摘要尽管人类克罗恩病的肠上皮（CD）证明了线粒体功能障碍和溃疡性结肠炎患者，针对线粒体功能障碍的炎症性肠病（IBD）疗法目前缺乏。人们普遍认为，细胞内线粒体池可通过移除来维持通过选择性自噬被称为线粒体的线粒体受损的线粒体。线粒体对肠道分泌细胞（Paneth，Goblet，肠内分泌）的功能，它富含线粒体维持戒备能源的秘书职能，但这尚待证明。 Paneth细胞功能障碍在CD患者的一部分中可以证明自噬缺陷可以驱动。但是，机制线粒体应激会导致炎症，而paneth细胞异常是未知的。禁止素1（PHB1）是内部线粒体膜（IMM）的主要成分蛋白调节电子传输链对ATP产生重要的功能。我们已经与villin产生了老鼠 - CREERT2诱导肠上皮细胞（IEC） - PHB1基因（PHB1ΔIEC）的特异性缺失，并表明这一点这些小鼠表现出发作性回肠炎，先于线粒体功能障碍，并早日paneth细胞缺陷 PHB1删除后。 PHB1ΔEIC小鼠中的Paneth细胞异常让人联想到Paneth细胞中缺乏的小鼠自噬。我们的中心假设是线粒体功能障碍随后抑制线粒体由肠上皮中PHB1丢失引起的导致细胞功能障碍和肠胃炎。我们将追求3 特定的目的是检验此假设：1。定义PHB1在线粒体功能障碍和赞助中的作用回肠炎，2。确定PHB1在线粒体诱导中的作用，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创新克罗恩的回肠炎。长期目标是确定靶向线粒体功能障碍是否是 IBD的有效治疗策略。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ptpn2: A Critical Regulator of Paneth Cell Homeostasis.

DOI：
10.1016/j.jcmgh.2023.03.010
发表时间：
2023-04
期刊：
Cellular and molecular gastroenterology and hepatology
影响因子：
7.2
作者：
Arianne L. Theiss
通讯作者：
Arianne L. Theiss

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer.

DOI：
10.1080/19490976.2019.1592421
发表时间：
2020-05-03
期刊：
Gut microbes
影响因子：
12.2
作者：
Jackson DN;Theiss AL
通讯作者：
Theiss AL

Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn's Disease.

DOI：
10.3390/cells10061349
发表时间：
2021-05-29
期刊：
Cells
影响因子：
6
作者：
Alula KM;Jackson DN;Smith AD;Kim DS;Turner K;Odstrcil E;Kaipparettu BA;Dassopoulos T;Venuprasad K;Feagins LA;Theiss AL
通讯作者：
Theiss AL

Mitochondria and Inflammatory Bowel Diseases: Toward a Stratified Therapeutic Intervention.