Role of URI in intestinal homeostasis and radiation enteropathy

• Autores: Almudena Chaves Pérez
• Directores de la Tesis: Nabil Djouder (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2019
• Idioma: inglés
• Número de páginas: 152
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Biología celular
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Intestine is the most rapidly-self renewing and proliferating organ in our body. Proper homeostasis in the gut is regulated by a strict balance between proliferation, differentiation and apoptosis and any deregulation may lead to the formation of enteropathies. Rapidly dividing cells present in the intestinal epithelium are sensitive to ionizing radiation (IR) used during abdominopelvic cancer radiotherapy. Death of intestinal epithelial cells following IR impairs intestinal regenerative capacity leading to the development of radiation enteropathy (RE) and gastrointestinal syndrome (GIS).

    Over 60% of patients with radiotherapeutically treated pelvic or abdominal tumors develop RE. Why some patients are more susceptible than others remain an unsolved question and quantitative biomarkers are needed to predict RE susceptibility and assess degrees of intestinal injury. Moreover, the cell types involved in intestinal regeneration following irradiation are highly debated.

    In this thesis project we show that increases in the co-chaperone unconventional prefoldin RPB5 interactor (URI), soon after irradiation protect mouse intestine, while its genetic ablation in intestinal epithelium disrupts organ’s architecture, recapitulating human GIS.

    URI specifically localizes and inhibits WNT/  catenin signaling pathway in stem-cell-like label retaining (LR) cells, essential for organ regeneration following IR and death of leucine-rich repeat-containing G-protein coupled receptor 5-high (Lgr5high) intestinal stem cells (ISCs). URI loss activates  catenin-induced c-MYC expression causing LR cells’ proliferation and DNA damage, sensitizing them to IR. Selective suppression of c-MYC and p53 axis restores organ architecture.

    Therefore, URI labels and maintains LR cell identity, a signaling platform essential for preservation of tissue architecture during IR.