Identifying a novel gene contributing to vascular maturation and its significance in cardiovascular diseases.
| Project/Area Number |
23659424
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Nara Medical University |
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Principal Investigator |
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| Project Period (FY) |
2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2011: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
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| Keywords | 血管新生 / 動脈分化 / TGFβスーパーファミリー / 肺高血圧 |
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| Research Abstract |
Members of the transforming growth factorβsuperfamily play essential roles in various aspects of embryonic development and physiological organ function. Among them, bone morphogenetic protein(BMP) 9 and BMP10 regulate embryonic vascular development by activating their endothelial receptor ALK1.ALK1-mediated intracellular signaling is implicated in the etiologies of human diseases such as HHT and pulmonary hypertension, but their downstream functional proteins are largely unknown. We identified gene X to be an embryonic endothelium-enriched gene activated by BMP9 and BMP10 through the ALK1 receptor. Gene X null mice showed embryonic lethality due to impaired differentiation of arterial endothelium and defects of vascular morphogenesis. The activity of Notch-and Akt-mediated signaling, which is essential for vascular development, was down regulated in gene X null mice, suggesting that the gene X deficiency leads to vascular demise, at least in part, through dysregulation of these signaling pathways. These data indicated that gene X play indispensable roles downstream of BMP9/BMP10-ALK1 signaling during endothelial differentiation and vascular morphogenesis.
Mutations in ACVRL1/ALK1 and BMPR2 cause hereditary hemorrhagic telangiectasia as well as pulmonary arterial hypertension in humans. Gene X might be involved in the mechanisms of these diseases as an additional causative gene or a modifier. To demonstrate this hypothesis we analyzed conditional KO mice of tamoxifen-induced inactivation of gene X. However cKO mice did not develop pulmonary hypertension spontaneously under unstressed conditions. We are investigating whether hypoxia induced severe pulmonary hypertension in cKO mice.
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Report
(2 results)
Research Products
(2 results)
