| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
|
|---|
| Research Abstract |
Rho family small GTPases regulate cell adhesion and cell motility. Among them, Rho participates in the regulation of smooth muscle contraction and cell migration. It has been suggested that the aberrant activation of Rho/Rho-kinase is associated with vasospasm, hypertension and progression of atherosclerosis via promotion of cell contraction and migration. However, involvement of other Rho .family GTPases such as Rac and Cdc42 has been less documented, even though Rac and Cdc42 are generally believed to be important in cell migration and adhesion and to cross talk with Rho signaling pathway.
1. Endothelial NOS (eNOS) produces NO, which is involved in various physiological functions of the cardiovascular system. eNOS is activated by phosphorylation at Ser1177, and by dephosphorylaton at Thr495. However, little is known about the protein kinases responsible for phosphorylation at Thr495. In this study, vie found that Rho-kinase phosphorylated eNOS at Thr495 both in vitro and endothelium,
… More
suggesting that Rbo-kinase can suppress NO production in endothelium through direct phosphorylation of eNOS.
2. A polarity complex of PAR-3, PAR-6, and aPAC functions in various cell polarization events, and PAR-3 interacts with RacGEF, STEP which leads to Rac activation. Rho and Rbo-kinase antagonize Rae in certain cell types, but the underlying mechanisms remain elusive. We here hind that Rho-kinase phospborylated PAR-3 at Thr333 and thereby disrupted its interaction with aPAC and PAR-6, and that Rlxykinam also phosphorylated STEF and modulated its functions. We propose that RholRbo-Kinase inhibits Rae activity through phosphorylation of PAR-3 and STEF.
3. Previous reports have shown that Rbo family GTPases are related to cardiovascular diseases. In this study, we hypothesized that there exist susceptibility genes f cardiovascular diseases in Rho family signaling molecules. We analyzed association of 38 gems (57 SNPs) of Rho family signaling molecules with coronary artery spasm, and found significant association of ARHGAP9 (Ala370Ser), which is negative regulator for Rac in vivo. Less
|
