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Studies on the Role of mTORC1 in Intestinal Inflammation and Epithelial Barrier Function, and Its Modulation by Curcumin and Piperine
mTORC1 is one of the central modulators of inflammation and tumorigenesis in the gastrointestinal tract. This is supported by the benefits afforded by pharmaceutical inhibitors of mTORC1 in experimental models of intestinal inflammation and tumorigenesis. Nonetheless, rapalog-based treatments can interfere with wound healing and regeneration of the gut tissue leading to increased mortality in experimental animals. This suggests that transiently repressing intestinal mTORC1 signaling with dietary bioactive molecules may eliminate certain adverse effects associated with rapalog therapy. Curcumin (CUR), a phytopolyphenol present in Curcuma longa (turmeric), is recognized for its anti-inflammatory and anti-neoplastic properties. The addition of piperine (PIP), an alkaloid from Piper nigrum (black pepper) perceived to enhance CUR bioavailability, may potentiate CUR’s inflammation and cancer preventative bioactivity in an mTORC1-dependent manner. This dissertation is dedicated to investigate (i) the role of mTORC1 signaling in the inflammatory response of intestinal epithelial cells (IEC) and macrophages placed under various pro-inflammatory conditions, (ii) the mechanism of mTORC1 inhibition by CUR in IEC, (iii) the effects of CUR, PIP and CUR+PIP combination on mTORC1-driven inflammatory response in IEC and macrophages, and (iv) the role of mTORC1 on epithelium barrier function. Results show that CUR and PIP, either alone or in combination significantly inhibited mTORC1 activity and mTORC1-driven inflammatory response in HT-29 goblet cells and THP-1 macrophages exposed to TNFα and LPS, respectively. However, in enterocyte-like Caco-2 cells exposed to macrophage-derived pro-inflammatory secretions, the downregulation of mTORC1 through RNA interference or rapamycin dosing increased TNFα gene expression while the constitutive activation of mTORC1 lowered cytokine gene expression. This revealed the immuno-regulatory properties of mTORC1 in IEC and macrophages placed in a pro-inflammatory microenvironment. Furthermore, the constitutive or transient downregulation of mTORC1 decreased the expression of tight junction proteins while increasing epithelial monolayer permeability to dextran of various sizes. Thus, the state of mTORC1 signaling in the gut should be taken into consideration when devising treatment strategies against intestinal inflammation and tumorigenesis.
Molecular biology|Biochemistry|Health sciences
Kaur, Harleen, "Studies on the Role of mTORC1 in Intestinal Inflammation and Epithelial Barrier Function, and Its Modulation by Curcumin and Piperine" (2020). ETD collection for University of Nebraska - Lincoln. AAI28031534.