| Project/Area Number |
17390117
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
KOJIMA Takashi (2007) Sapporo Medical University, School of Medicine, Associate Professor (30260764)
小山内 誠 (2005-2006) 札幌医科大学, 医学部, 講師 (60381266)
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| Co-Investigator(Kenkyū-buntansha) |
CHIBA Hideki Sapporo Medical University, School of Medicine, Associate Professor (00295346)
TOBIOKA Hrotoshi Sapporo Medical University, School of Medicine, Researcher (90291559)
MURATA Masaki Sapporo Medical University, School of Medicine, Instructor (10404592)
小島 隆 札幌医科大学, 医学部, 助教授 (30260764)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥15,660,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2007: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2006: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2005: ¥6,000,000 (Direct Cost: ¥6,000,000)
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| Keywords | human nasal mucosa / tight junction / claudin / retinoic acid / HNF-4α / glial cell / diabetic retinopathv / Ca absorption / 鼻アレルギー / TSLP / Toll-like receptor / オクルジン / クローディン / occludin / アポトーシス / シグナル伝達 / フェンス機能 / 上皮細胞極性 |
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| 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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