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:
  • 金额:
    $ 34.93万
  • 依托单位:
  • 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

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

项目成果

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ARIANNE L THEISS其他文献

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{{ truncateString('ARIANNE L THEISS', 18)}}的其他基金

Adipose Tissue Extracellular Vesicles in Colorectal Tumorigenesis
脂肪组织细胞外囊泡在结直肠肿瘤发生中的作用
  • 批准号:
    10655305
  • 财政年份:
    2022
  • 资助金额:
    $ 34.93万
  • 项目类别:
Adipose Tissue Extracellular Vesicles in Colorectal Tumorigenesis
脂肪组织细胞外囊泡在结直肠肿瘤发生中的作用
  • 批准号:
    10367993
  • 财政年份:
    2022
  • 资助金额:
    $ 34.93万
  • 项目类别:
Mitochondrial Dysfunction and Mitophagy in Ileitis
回肠炎中的线粒体功能障碍和线粒体自噬
  • 批准号:
    9982322
  • 财政年份:
    2019
  • 资助金额:
    $ 34.93万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 34.93万
  • 项目类别:
Mitochondrial Dysfunction and Mitophagy in Ileitis
回肠炎中的线粒体功能障碍和线粒体自噬
  • 批准号:
    10557967
  • 财政年份:
    2019
  • 资助金额:
    $ 34.93万
  • 项目类别:
Mitochondrial Dysfunction and Mitophagy in Ileitis
回肠炎中的线粒体功能障碍和线粒体自噬
  • 批准号:
    10450818
  • 财政年份:
    2019
  • 资助金额:
    $ 34.93万
  • 项目类别:
Maintenance of intestinal epithelial cell homeostasis by prohibitin
抑制素维持肠上皮细胞稳态
  • 批准号:
    8737248
  • 财政年份:
    2013
  • 资助金额:
    $ 34.93万
  • 项目类别:
Maintenance of intestinal epithelial cell homeostasis by prohibitin
抑制素维持肠上皮细胞稳态
  • 批准号:
    8633115
  • 财政年份:
    2013
  • 资助金额:
    $ 34.93万
  • 项目类别:
Role and function of prohibitin in intestinal inflammation
抑制素在肠道炎症中的作用和功能
  • 批准号:
    8222138
  • 财政年份:
    2010
  • 资助金额:
    $ 34.93万
  • 项目类别:
Role and function of prohibitin in intestinal inflammation
抑制素在肠道炎症中的作用和功能
  • 批准号:
    8418743
  • 财政年份:
    2010
  • 资助金额:
    $ 34.93万
  • 项目类别:

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