| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Type III sodium-dependent inorganic phosphate (Pi) transporter, Pit-1 (Glvr-1), is a ubiquitous protein. Its expression, however, was found to increase in a subpopulation of hypertrophic chondrocytes suggesting a role in bone development. In addition to bone-froming cells, accumulating evidences suggest that the phosphate uptake through Pit-1 induces apoptosis of several types of cells. Among them, Pit-1 plays an important role in the pathogenesis of atherosclerosis, and we have reported that Pit-1 was expressed in aortic smooth muscle cells. These findings suggest that over expression of Pit-1 may affect the development of different organs, and that Pit-1 over expression also induces atherosclerosis in aged animals. In this research, we have at first shown that PDGF-BB and arginine vasopressin are potent and selective stimulatosr of Pi transport in vascular smooth muscle cells, and that the mechanism responsible for this effect is not mediated by MAP kinase, but involves activation of PKC,PI 3-kinase and S_6 kinase. BMP-2 also stimulates Pi transport activity via a selective increase in expression of type III Pi transporters Pit-1 in osteoblast-like cells. This effect is mediated by the JNKpathway and plays an essential role in bone matrix calcification induced by BMP-2. TEM analysis revealed that thin and relatively long crystals are deposited in association with collagen fibrils, an observation that is consistent with physiological mineralization.
We here developed Pit-1-overexpressed transgenic rats. The results suggest us that Pit-1 overexpression and high cellular Pi transport does not influence skeletal development but likely disturbs a metabolic process. That is, it is associated with an early onset of cataract and alteration in the integrity of the glomerular system leading to a nephrotic syndrome.
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