The apically located inter-cellular tight junctions (TJ) within the intestinal epithelium act as a paracellular barrier and prevent permeation of noxious luminal antigens. Loss of intestinal TJ barrier function is a key pathogenic factor in intestinal disorders and inflammatory bowel disease (IBD). Emerging evidence shows that defects in autophagy play an important role in the susceptibility, etiology, and progression of IBD. Although clinical data and animal studies show a direct link between defective intestinal TJ barrier and intestinal inflammation in IBD patients and animal models of IBD, the role of autophagy in the regulation of intestinal epithelial TJ barrier remains unknown. Our preliminary studies indicated that autophagy plays a key role in the enhancement of intestinal TJ barrier. Specifically, autophagy reduces paracellular TJ permeability by degradation of the pore forming tight junction protein claudin-2 and increasing protein levels of barrier protective transmembrane TJ protein occludin. Induction of autophagy causes a selective increase in lysosomal targeting of claudin-2 from the membrane and causes an increase in membrane retention of occludin. Thus, our central hypothesis is that autophagy selectively modulates TJ membrane protein composition to induce an enhancement of the intestinal TJ barrier. The overall specific aims of this application are:
Specific Aim 1. To delineate the intracellular vesicular trafficking mechanisms in autophagy-induced enhancement of intestinal epithelial TJ barrier.
Specific Aim 2. To elucidate the role of intracellular signaling in autophagy regulation of intestinal TJ barrier.
Specific Aim 3. To delineate the role of autophagy in intestinal TJ barrier function and inflammation in animal models of IBD. This proposal will provide novel insights into the crucial role that autophagy plays in the homeostasis of intestinal barrier and bridge the gap in scientific knowledge that will be important for therapeutic efforts against IBD.
The tight junctions (TJ) present between intestinal epithelial cells act as a paracellular barrier and serve as a first line of defense against permeation of noxious antigens present in the intestinal lumen. Defective intestinal tight junction (TJ) barrier allows penetration of harmful luminal antigens in the gut which in turn leads to intestinal inflammation. Autophagy is a normal process that helps cell survival by recycling the nutrients and energy via degradation and turnover of the misfolded or unnecessary proteins. Recent studies have shown that mutations in autophagy related genes and defects in autophagy process are risk factors for inflammatory bowel disease (IBD) including Crohn disease (CD). The purpose of this grant application is to elucidate the mechanisms involved in autophagy-mediated enhancement of the intestinal epithelial tight junction barrier. Clinically, maintenance of mucosal barrier in the intestine is critical for the prevention of intestinal mucosal damage and therapeutic success in IBD cases. This study will provide novel insights into the crucial role of autophagy in enhancement of intestinal barrier and prevention of intestinal inflammation.
| Tasnim, Humayra; Fricke, G Matthew; Byrum, Janie R et al. (2018) Quantitative Measurement of Naïve T Cell Association With Dendritic Cells, FRCs, and Blood Vessels in Lymph Nodes. Front Immunol 9:1571 |
| Castillo, Eliseo F; Zheng, Handong; Yang, Xuexian O (2018) Orchestration of epithelial-derived cytokines and innate immune cells in allergic airway inflammation. Cytokine Growth Factor Rev 39:19-25 |
| Zheng, Handong; Wu, Dandan; Wu, Xiang et al. (2018) Leptin Promotes Allergic Airway Inflammation through Targeting the Unfolded Protein Response Pathway. Sci Rep 8:8905 |
| Deretic, Vojo; Klionsky, Daniel J (2018) Autophagy and inflammation: A special review issue. Autophagy 14:179-180 |
| Zhang, Xing; Luo, Yan; Wang, Chunqing et al. (2018) Adipose mTORC1 Suppresses Prostaglandin Signaling and Beige Adipogenesis via the CRTC2-COX-2 Pathway. Cell Rep 24:3180-3193 |
| Kumar, Suresh; Jain, Ashish; Farzam, Farzin et al. (2018) Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins. J Cell Biol 217:997-1013 |
| Claude-Taupin, Aurore; Bissa, Bhawana; Jia, Jingyue et al. (2018) Role of autophagy in IL-1? export and release from cells. Semin Cell Dev Biol 83:36-41 |
| Deretic, Vojo; Levine, Beth (2018) Autophagy balances inflammation in innate immunity. Autophagy 14:243-251 |
| Jia, Jingyue; Abudu, Yakubu Princely; Claude-Taupin, Aurore et al. (2018) Galectins Control mTOR in Response to Endomembrane Damage. Mol Cell 70:120-135.e8 |
| Choi, Seong Won; Gu, Yuexi; Peters, Ryan Scott et al. (2018) Ambroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity. Antimicrob Agents Chemother 62: |
Showing the most recent 10 out of 11 publications
