| Budget Amount *help |
¥70,300,000 (Direct Cost: ¥70,300,000)
Fiscal Year 2005: ¥11,000,000 (Direct Cost: ¥11,000,000)
Fiscal Year 2004: ¥11,500,000 (Direct Cost: ¥11,500,000)
Fiscal Year 2003: ¥17,000,000 (Direct Cost: ¥17,000,000)
Fiscal Year 2002: ¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2001: ¥18,000,000 (Direct Cost: ¥18,000,000)
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| Research Abstract |
(1) Mechanism of substrate recognition : By constructing of ABCC1/ABCC2 chimeric proteins and examining their the kinetic properties for LTC_4 transport in inside-out membrane vesicles, we have obtained the results suggesting that Membrane Spanning Domain (MSD)1 are involved in substrate affinity and that the COOH-terminal half is exchangeable between two proteins. Because, basic and/or charged residues in MSD2 and MSD3 but not in MSD1 have been reported repeatedly to be involved in substrate binding, our results shows that portion contributing in substrate affinity would be different from that of substrate binding itself.
(2) Sorting mechanisms for intracellular localization : We narrowed down the region participating in determination of apical-basolateral localization to the second membrane spanning domain 2(MSD2)and surrounding region.
(3) To evaluate the effect of ABCB1 in intestinal tumorigenesis directly, we generated Abcbla-disrupted mice with an Apc^<min/+> background, an animal model for human familial adenomatous polyposis, and examined whether polyp formation were affected by the absence of functional ABCB1. The number and size of intestinal polyps in Abcbla^<-/->, Apc^<min/+> mice was significantly smaller than the number in Abcbla^<+/+>, Apc^<Min/+> mice. We then analyzed association between genetic variations in the ABCBI gene and cororectal cancer risk. By case-control study using 460 colorectal cancer patients and 783 healthy volunteers, we obtained the results indicating that the cancer risk of individuals who's genetic background is associated with low ABCB1 level is half of the individuals with lower ABCB1 genetic background.
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