| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Outline of Final Research Achievements |
Recently, Kelch-like 3 (KLHL3) and Cullin3 (Cul3) were identified as novel causative genes for the hereditary hypertensive disease, pseudohypoaldopsteronism type II (PHAII). To elucidate the relationship between KLHL3/Cul3 and the WNK signaling pathway, we analyzed protein overexpression system in cultured cells and generated mutant Cul3 knock-in mice. As a result, we found that KLHL3 was associated with the ubiquitination of WNK1/4, and that mutant KLHL3 interfered with WNK ubiquitination resulting in the hyper-activation of the WNK signaling pathway, leading to the development of hypertension. In the mutant Cul3 knock-in mice, decreased expression of Cullin3 was observed, whereas PHAII-like phenotype was not replicated. This result suggested that mere heterozygous deletion of Cul3 was not sufficient for the onset of PHAII and that the mutant Cul3 protein with the deletion of exon9 might have a dominant-negative function.
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