Mitochondrial Dysfunction and Mitophagy in Ileitis

Information

  • Research Project
  • 9789256
  • ApplicationId
    9789256
  • Core Project Number
    R01DK117001
  • Full Project Number
    5R01DK117001-02
  • Serial Number
    117001
  • FOA Number
    PA-18-484
  • Sub Project Id
  • Project Start Date
    9/20/2018 - 5 years ago
  • Project End Date
    7/31/2023 - 10 months ago
  • Program Officer Name
    PERRIN, PETER J
  • Budget Start Date
    8/1/2019 - 4 years ago
  • Budget End Date
    7/31/2020 - 3 years ago
  • Fiscal Year
    2019
  • Support Year
    02
  • Suffix
  • Award Notice Date
    7/23/2019 - 4 years ago

Mitochondrial Dysfunction and Mitophagy in Ileitis

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.

IC Name
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
  • Activity
    R01
  • Administering IC
    DK
  • Application Type
    5
  • Direct Cost Amount
    231318
  • Indirect Cost Amount
    132693
  • Total Cost
    364011
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    847
  • Ed Inst. Type
  • Funding ICs
    NIDDK:364011\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CIMG
  • Study Section Name
    Clinical, Integrative and Molecular Gastroenterology Study Section
  • Organization Name
    BAYLOR RESEARCH INSTITUTE
  • Organization Department
  • Organization DUNS
    145745022
  • Organization City
    DALLAS
  • Organization State
    TX
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    75201
  • Organization District
    UNITED STATES