| Budget Amount *help |
¥123,110,000 (Direct Cost: ¥94,700,000、Indirect Cost: ¥28,410,000)
Fiscal Year 2004: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000)
Fiscal Year 2003: ¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2002: ¥30,940,000 (Direct Cost: ¥23,800,000、Indirect Cost: ¥7,140,000)
Fiscal Year 2001: ¥48,880,000 (Direct Cost: ¥37,600,000、Indirect Cost: ¥11,280,000)
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| Research Abstract |
α-Tocopherol transfer protein(α-TTP) is a product of the causative gene for familial isolated vitamin E deficiency. Secretion of α-tocopherol from hepatocytes by α-TTP is essential for the maintanance of plasma α-tocopherol concentrations. There are six α-TTP point mutations known to cause AVED. Among these mutations, R59W is of particular interest. Although the α-tocopherol binding capacities of wild-type and R59W α-TTP were almost the same, patients with this mutation show undetectable plasma vitamin E levels and a severe phenotype. We have found that wild-type α-TTP binds to PIPs, but R59W α-TTP cannot bind to them. Moreover, the in vitro α-tocopherol transfer activity of the wild-type α-TTP increased with the increasing content of PIPs in the acceptor liposomes, while the transfer activity by R59W α-TTP did not. From these results, we suggest that α-tocopherol transferred to the PIPs enriched inner leaflet of the plasma membrane by α-TTP is readily secreted extracellularly by a cer
… More
tain ABC transporter.
Squalene epoxidase converts squalene to squalene 2,3-oxide. Recently, we cloned the cDNA of SPF(Supernatant Protein Factor), a cytosolic activator of squalene epoxidation. In this study, we established SPF-deficient mice to analyze the cholesterol metabolism in these mice. SPF-deficient mice were normally developed. However, we observed that fibrate, an anti-atherosclerosis drug significantly decreases plasma cholesterol level in SPF-deficient mice. These data indicate that SPF functions in maintaining cholesterol homeostasis in a fasting state, and that SPF is a promising target for cholesterol-lowering therapy.
25-hydroxycholesterol binds to a specific cytosolic receptor termed oxysterol-binding protein(OSBP). In mammalian cells, upon binding of 25-hydroxycholesterol, OSBP translocates from cytoplasm to the Golgi apparatus. A family of OSBP homologues, called ORP family, has been identified in a variety of species. In mammal, the family includes 12 genes. Most of their physiological functions and ligands remain to be elucidated. We cloned the all members of the human ORP family and analyzed their subcellular localizations in HeLa cells. Each protein shows different subcellular localization pattern including plasma membrane, ER and cytosolic vesicles, suggesting that the ORP family members are functionally distinct. Less
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