Increased mucosal permeability is a key characteristic of the inflammatory bowel disease (IBD). The claudin family of proteins constitutes the tight junctions (TJs), which are the sole determinants of the paracellular permeability in an intact epithelium. Importantly, a common finding from the analysis of the IBD (Crohn's and Ulcerative Colitis) patient samples and related animal models is that claudin-2 expression is highly upregulated in the IBD. In the claudin family, Claudin-2 is unique as its expression correlates with the epithelial leakiness. However, it is also noteworthy that the colonic claudin-2 is expressed among the undifferentiated colonocytes at the crypt base, the proliferative zone. Furthermore, outcome from our preliminary studies and recently published studies from other labs suggest potential correlation of claudin-2 expression with the colonic epithelial cell proliferation and/or migration. It is further noteworthy that claudin-2 is a target of the Wnt/?-catenin signaling. However, role of claudin-2 in the pathogenesis of IBD is not known. To investigate, we generated Villin-claudin-2 transgenic (Cl-2Tg) mice that overexpress claudin-2 in the colon, a condition similar to the IBD. Our studies using these mice have provided novel outcomes: 1) Colonic epithelial permeability in Cl-2Tg mice is significantly increased compared to the WT littermates (p<0.05);2) the colon and crypt lengths in Cl-2Tg mice are significantly increased compared to the wild type (WT) littermates (p<0.001 for both);and 3) Cl-2Tg mice are significantly protected from experimental-colitis [induced using dextran sodium sulfate (DSS, 4% w/v in drinking water)] compared to WT littermates (p<0.001). Our further data show sharp decreases in the DSS-induced expressions of proinflammatory cytokines including IL-1a, IL- 1?, TNF-a in Cl-2Tg mice compared to the WT littermates. On the other hand, gene expressions related with proliferation were upregulated in the DSS-treated Cl-2Tg mice compared to the DSS-treated WT littermates. Taken together, we postulate that claudin-2 plays an important role in the regulation of colonic homeostasis. We further hypothesize that immune adaptation/tolerance due to the constitutive increase in the mucosal permeability and/or modulations of the colonic epithelial cell proliferation/apoptosis or combination of both underlie the protection from DSS-colitis in Cl-2Tg mice. To test our hypothesis, we have proposed following specific aims: 1) To determine whether claudin-2 TG mice are protected against mucosal inflammation and disease;2) To determine the role of claudin-2 in colitis-associated regeneration, repair and colitis-associated cancer;and 3) To determine the cellular and molecular mechanism/s underlying protection from colitis in claudin-2 TG mice. We anticipate that our studies will provide valuable and clinically relevant information that will have direct impact upon the understanding of the regulation of IBD pathogenesis and its progression to cancer, and will create potential new opportunities for therapeutic interventions.
We will investigate the role of mucosal permeability in colonic inflammation using mice engineered to over- express claudin-2, a tight junction integral protein. We will further determine the role of claudin-2 in the regulation of colonic homeostasis, epithelial cell proliferation and a causal role in the IBD-associated cancer.
|Kanvinde, Shrey; Chhonker, Yashpal Singh; Ahmad, Rizwan et al. (2018) Pharmacokinetics and efficacy of orally administered polymeric chloroquine as macromolecular drug in the treatment of inflammatory bowel disease. Acta Biomater 82:158-170|
|Ahmad, R; Sorrell, M F; Batra, S K et al. (2017) Gut permeability and mucosal inflammation: bad, good or context dependent. Mucosal Immunol 10:307-317|
|Singh, Amar B; Uppada, Srijayaprakash B; Dhawan, Punita (2017) Claudin proteins, outside-in signaling, and carcinogenesis. Pflugers Arch 469:69-75|
|Ahmad, R; Kumar, B; Chen, Z et al. (2017) Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/?-catenin signaling. Oncogene 36:6592-6604|
|Ahmad, Rizwan; Rah, Bilal; Bastola, Dhundy et al. (2017) Obesity-induces Organ and Tissue Specific Tight Junction Restructuring and Barrier Deregulation by Claudin Switching. Sci Rep 7:5125|
|Ahmad, Rizwan; Kumar, Balawant; Pan, Kaichao et al. (2017) HDAC-4 regulates claudin-2 expression in EGFR-ERK1/2 dependent manner to regulate colonic epithelial cell differentiation. Oncotarget 8:87718-87736|
|Bhat, Ajaz A; Ahmad, Rizwan; Uppada, SrijayaPrakash B et al. (2016) Claudin-1 promotes TNF-?-induced epithelial-mesenchymal transition and migration in colorectal adenocarcinoma cells. Exp Cell Res 349:119-127|
|Singh, Amar B (2016) EGFR-Signaling and Autophagy: How they Fit in the Cancer Landscape. J Adenocarcinoma 1:|
|Singh, Amar B; Dhawan, Punita (2015) Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact. Semin Cell Dev Biol 42:58-65|
|Bhat, A A; Pope, J L; Smith, J J et al. (2015) Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. Oncogene 34:4570-80|
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