| Research Abstract |
In this project, we have been trying to expand understanding of molecular regulation of tight junctions to human diseases, as follows.
1. Orphan nuclear receptor HNF-4alpha is shown to induce various kinds of tight junction proteins including claudins and microvilli component EBP-50, resulted in formation of microvilli as well as tight junctions.
2. Permeability of blood-retinal barrier is well known to increase with advance of diabetic retinopathy. We showed that retinoic acid, in particular RAR-alpha ligand, prevent the increase of the permeability by production of GDNF in astrocytes.
3. The epithelial barrier of the upper respiratory tract, which is the first site of exposure to inhaled antigens, plays a crucial role in host defense in terms of innate immunity. The epithelium of the nasal mucosa forms a continuous barrier against a wide variety of exogenous antigens by tight junctions. We first found that expression of dendritic cell activator TSLP is significantly increased in patients with nasal allergy. Thus to study the mechanisms involved in nasal allergy, we first established a culture method to passage human nasal epithelial cells using hTERT. These cultures express claudin-1, -4, -7, like the cells in vivo. Using these cultures, we demonstrate that TLR-2 ligand induces TSLP production. On the other hand, we found that TSLP induced expression of claudin-7. These results suggest dendritic cells tightly contact with nasal epithelium.
4. Ca^<2+> is considered to be absorbed across intestinal epithelial monolayers via transcellular and paracellular pathways. We show, by using vitamin V receptor knockout mice, RNA interference and overexpression strategies, that claudin-2 and claudin-12 contribute to paracellular Ca^<2+> absorption in intestinal epithelial cells. We also provide evidence showing that expression of claudins 2 and 12 is upregulated in enterocytes in vitro and in vivo by 1α,25 (OH)_2D_3 through its receptor VDR.
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