EGF RECEPTOR IN SMOOTH MUSCLE CELL FUNCTION

肝素和相关硫酸乙酰肝素糖胺聚糖抑制平滑肌细胞（SMC）增殖和迁移。这一观察结果是有意义的，因为硫酸乙酰肝素蛋白多糖可能在调节正常动脉壁中SMC的生长状态中起作用。肝素抑制凝血酶和血清对SMC的激活作用，但对PDGF-BB无抑制作用。在初步的实验中，我们已经表明，凝血酶信号传导部分介导的肝素结合EGF样生长因子（HB-EGF），激活的EGF受体（EGFR），并没有被肝素阻断。本研究的主要目的是验证三个假设：1。EGFR活化是SMC在体外和体内迁移所必需的; 2. PDGF-BB和凝血酶利用不同的EGFR反式激活机制; 3. EGFR激活诱导硫酸乙酰肝素蛋白聚糖的表达，然后调节EGFR功能。我们提出了一种结合体外和体内的方法，使用培养的狒狒和大鼠SMC，球囊损伤的大鼠颈动脉，和药理学策略，用于调节HB-EGF，EGFR，PDGFR和凝血酶受体功能。

Heparin and related heparan sulfate glycosaminoglycans inhibit smooth muscle cell (SMC) proliferation and migration. This observation is of significance because heparan sulfate proteoglycans may play a role in regulating the growth state of SMCs in the normal arterial wall. Heparin inhibits SMC activation by thrombin and serum but not PDGF-BB. In preliminary experiments, we have shown that thrombin signaling is mediated in part by heparin-binding EGF-like growth factor (HB-EGF), activation of the EGF receptor (EGFR), and is not blocked by heparin. The primary objective of this research program is to test three hypotheses: 1. EGFR activation is required for SMC migration in vitro and in vivo; 2. PDGF-BB and thrombin utilize different mechanisms for EGFR transactivation; 3. EGFR activation induces the expression of heparan sulfate proteoglycans that then modulate EGFR function. We propose a combined in vitro and in vivo approach using cultured baboon and rat SMCs, the balloon-injured rat carotid artery, and pharmacological strategies for modulating HB-EGF, EGFR, PDGFR, and thrombin receptor function.