A Putative Heparin Receptor in Smooth Muscle Cells

描述(申请人提供)：血管平滑肌细胞过度生长 是血管疾病晚期的标志，并有助于最终 阻塞受影响的动脉。肝素被证明可以减缓平滑肌细胞的生长 体外生长和选定的体内研究。肝素对血管通畅的影响 肌肉细胞的解释理论包括肝素受体、肝素 与生长因子的相互作用和肝素的内吞作用。私家侦探S的数据 实验室发现涉及cGMP的肝素受体和信号转导 产生和特异的MAPK磷酸酶。这项拟议的研究旨在测试 肝素对培养的肝素敏感血管平滑肌作用的假说 细胞将导致MAPK通路上游信号步骤的活性降低，并 肝素与肝素相互作用降低SAPK通路活性 之前在P.L.S实验室发现的受体。拟议的研究将 评估肝素及其受体对PDGF上游信号的影响 通过SOS，RAS和RAF使用肝素，抗肝素受体抗体， CGMP类似物和PKG阻滞剂。肝素对MAPK活性影响的研究 在整个细胞周期中将评估是否有额外的MAPK活性 在整个周期中是减少的，或者肝素的作用是否只在胃肠道起作用 从GO检查点放行。拟议的研究将评估信令在 血管紧张素II激活的反应，以确定肝素是否影响 平滑肌细胞MAPK信号转导仅限于MAPK激活 对生长因子的反应，或者可以调制MAPK信号而不考虑激活 系统。这些研究还将包括评估肝素中应激激酶的活性。 来检查这些平行的通路是否被 根据我们关于肝素的机制的信息，肝素是可以预期的 MAPK活性降低。最后，这项研究将继续开展工作，以确定 克隆肝素受体，为进一步研究肝素受体的作用机制奠定基础 肝素作用。这些研究将共同证实肝素的重要性。 肝素受体诱导血管平滑肌细胞的变化，并将提供一种 了解肝素如何改变敏感血管的重大进展 平滑的肌肉细胞。

DESCRIPTION (provided by applicant): The overgrowth of vascular smooth muscle cells is a hallmark of the late stages of vascular disease and contributes to the eventual blocking of affected arteries. Heparin has been shown to slow smooth muscle cell growth in vitro and in selected in vivo studies. Heparin effects on vascular smooth muscle cells have been explained by theories including heparin receptors, heparin interaction with growth factors and endocytosis of heparin. Data from the P.I.'s laboratory implicate a heparin receptor and signal transduction involving cGMP production and specific MAPK phosphatases. The proposed research aims to test the hypothesis that heparin treatment of cultured heparin-sensitive vascular smooth muscle cells will result in decreased activity of upstream signal steps in the MAPK pathway and decreased SAPK pathway activity through heparin's interaction with the heparin receptor previously identified in the P.l.'s laboratory. The proposed research will evaluate heparin and heparin receptor effects on upstream signaling from the PDGF receptor through SOS, Ras, and Raf using heparin, anti-heparin receptor antibodies, cGMP analogs, and PKG blockers. Studies of heparin effects on MAPK activity throughout the cell cycle will evaluate whether additional MAPK activity seen throughout the cycle is decreased, or whether the heparin effects are only at the Gi release from GO check point. The proposed research will evaluate signaling in response to Angiotensin II activation to determine whether the heparin effects on smooth muscle cell MAPK signal transduction are limited to MAPK activation in response to growth factors, or can modulate MAPK signaling regardless of activation system. These studies will also include evaluation of stress kinase activity in heparin treated smooth muscle cells to examine whether these parallel pathways are altered by heparin as might be expected based on our information about the mechanism by which MAPK activity is decreased. Finally, this study will continue work aimed at identifying a clone for the heparin receptor to enable further studies regarding the mechanism of heparin action. Together these studies will confirm the importance of the heparin receptor in heparin induced changes in vascular smooth muscle cells and will provide a significant advancement in understanding of how heparin alters sensitive vascular smooth muscle cells.