| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
HB-EGF is a member of the EGF family of growth factors that has a high affinity for heparin and heparan sulfate (HS), and is known to be involved in cardiac valve development. HB-EGF suppresses proliferation of mesenchymal cells in this process. In this research, we investigated the regulatory mechanisms involved in the HB-EGF-induced cell growth inhibition in cardiac valve development (valvulogenesis).
1) Significance of the interaction of HB-EGF with HS-proteoglycans (HSPGs) in valvulogenesis. We generated the knock-in mice expressing a heparin-binding domain-truncated form (HB^<Δbb>) of the molecule, which lacks HS-binding activity. HB^<Δbb/Δbb> mice developed enlarged cardiac valves with abnormal hyperproliferation of the mesenchymal cells during valvulogenesis, phenotypes similar to that in HB-EGF null (HB^<dcl/del>) mice. In vitro study using endocardial cushion explants culture demonstrated requirement of HB-EGF-HSPGs interaction for HB-EGF-EGFR signal-mediated growth-inhibition
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of mesenchymal cells. These results indicate that interaction of HB-EGF with HSPGs promotes growth-inhibition of differentiated mesenchymal cells in developing cardiac valve. (Manuscript in preparation)
2) HB-EGF and Snail signaling negatively regulates proliferation of mesenchymal cells during valvulogenesis. We found that the expression of Snail was dramatically decreased in HB^<del/del> mutant valves during remodeling process in valvulogenesis. Exogenously introduced Snail and HB-EGF into the HB^<del/del> mutant valves were able to rescue the overproliferation of mesenchymal cells. These results demonstrate that HB-EGF inhibits proliferation of mesenchymal cells via Snail during valve remodeling. (Manuscript in preparation)
3) Perinatal distal lung development: another physiological process in which HB-EGF induces cell growth inhibition. HB^<del/del> newborns displayed abnormally thick alveolar walls, occurring from E18.5, that reduced the terminal saccular space area, with a increase in cell proliferation, indicating that HB-EGF suppresses distal lung cell proliferation. Furthermore, an analysis of alveolar morphology and proliferation in HB-EGF and TGFα double mutant newborns revealed that HB-EGF and TGFa function synergistically in this suppression. Crosses between HB^<del/del> mice and waved 2 mice, a hypomorphic EGFR mutant strain, suggest that HB-EGF and EGFR cooperate in this process. Thus, HB-EGF has a suppressive function that contributes to decelerating distal lung cell proliferation synergistically with TGFa through EGFR in perinatal distal lung development. (Dev. Dyn. 2008, 237, 247-258) Less
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