2017 Fiscal Year Research-status Report
Morphometrical and quantitative transcriptome analyses of C-C chemokine receptor 5 in functional structure of osteoclasts
| Project/Area Number |
16K20412
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| Research Institution | Ehime University |
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Principal Investigator |
李 智媛 愛媛大学, プロテオサイエンスセンター, 助教(特定教員) (70711274)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | chemokine receptor / CCR5 / osteoclast |
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| Outline of Annual Research Achievements |
This study demonstrated that pathophysiological roles of CCR5 in bone metabolism in vivo and in vitro system.
Since C-C chemokine receptor 5 (CCR5) was discovered to be a critical co-receptor for macrophage-tropic HIV, the inhibitors against CCR5 such as Maraviroc have been used for the HIV patients. Epidemiological and pathological findings in human studies reported that functional loss in CCR5 correlate with the resistance to bone destruction diseases as well as HIV transmission.
The blockade of CCR5 using its specific antibodies impaired in vitro human osteoclastogenesis with disorganized actin rings, but not osteoblastogenesis. Ccr5-deficient (Ccr5-/-) mice with dysfunctional osteoclasts were resistant to osteoporotic stimulation via the administration of receptor activator of nuclear factor kappa-B ligand (RANKL), which induces osteoporosis independently of the inflammatory and immunomodulatory responses. Furthermore, the CCR5-mediated pathway in osteoclasts transcriptionally and post-translationally enhanced the integrin-mediated and chemokine pathways. This study experimentally provides further evidence that CCR5 plays an essential role in bone destructive diseases through the functional regulation of osteoclasts, thus suggesting the skeletal benefit of CCR5-targetting therapy.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
All experiments (animal, cell culturing and molecular work) proceeded as planed. We have finished reporting to the journal related this research.
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| Strategy for Future Research Activity |
Our recent report demonstrated that a chemokine receptor CCR5 is required for the osteoclast function and balance of bone remodeling. We found targets of CCR5-mediated signal using proteomics approach. We will expand this research using knockout (cKO) mice generated by X-gene flowed mice with osteoclast specific Cre-recombinase mice. Since osteoclast functions as a bone remodeling balancer, our genome-wide approaches will find bio signals as potential therapeutic targets, thus contributing for the bone therapy of regeneration and metabolism.
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| Causes of Carryover |
Since we found the new target gene during the research, we will use this to make perform additional profound analysis. It can be more apparent the relationship between molecular mechanism and bone metabolism of osteoclast function.
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Author(s)
Morita M, Nagaoka H, Ntege E, Kanoi B, Ito D, Nalata T, Lee JW, Tokunaga T, Torii M, Tsuboi T, Takashima E.
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Journal Title
Scientific Reports
Volume: 8
Pages: 3696
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene expression.2018
Author(s)
Yamashita M, Inoue K, Saeki N, Ideta-Otsuka M, Yanagihara Y, Sawada Y, Sakakibara I, Lee JW, Ichikawa K, Kamei Y, Iimura T, Imai Y.
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Journal Title
Development
Volume: 145
Pages: 157412
DOI
Peer Reviewed / Int'l Joint Research
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