Syndecan-1 and the Arterial Response to Injury

描述（由申请人提供）：多配体蛋白聚糖（多配体蛋白聚糖-1、-2、-3和-4）是跨膜乙酰肝素和硫酸软骨素蛋白聚糖（HSPG），由动脉平滑肌细胞（SMC）表达，在受损动脉中受到调节，结合各种生长因子和细胞外基质（ECM）组分，是细胞-生长因子、细胞-细胞和细胞-ECM相互作用的重要调节剂。虽然已知硫酸乙酰肝素糖胺聚糖和肝素通过抑制SMC迁移和增殖以及通过改变SMC ECM的产生来抑制损伤诱导的内膜增厚，但多配体聚糖在SMC生长和对动脉损伤的反应中的作用尚未确定。我们最近发现，内膜增厚和中膜增生显着增加，在损伤的颈动脉syndecan-1 null小鼠。此外，这些小鼠培养的动脉SMC表达更高水平的PDGF-B mRNA，并且响应于PDGF-BB、血清、EGF、FGF 2和凝血酶，比野生型小鼠的SMC迁移和增殖更多。PDGF-B链和PDGFR-β的siRNA敲低其各自的靶标并抑制凝血酶、PDGF-BB和血清诱导的SMC增殖。这些发现向我们证明syndecan-1是动脉SMC生长的负调节因子。该提案的主要目标是确定syndecan-1的转录是如何调节的，以及syndecan-1如何控制PDGF-B对生长因子的诱导。具体目标是：1.明确syndecan-1在体内外的调控机制; 2.确定syndecan-1抑制凝血酶介导的PDGF-B链诱导的机制; 3.在结构-功能研究中确定多配体蛋白聚糖-1胞外域、胞质结构域或两者是否是多配体蛋白聚糖-1抑制PDGF-B诱导和细胞生长所必需的。拟议的研究应该提供关于syndecan-1的新见解，这将成为预防再狭窄的药理学发展的基础，再狭窄是一个影响大量接受冠状动脉支架成形术的患者的问题。 公共卫生相关性：拟议的研究应该提供新的见解syndecan-1，一种由平滑肌细胞表达的分子，抑制动脉损伤后内膜增厚的形成。这些观察结果将为开发预防再狭窄的药理学奠定基础，再狭窄是一个影响大量接受冠状动脉支架成形术的患者的问题。

DESCRIPTION (provided by applicant): Syndecans (syndecans-1, -2, -3, and -4) are transmembrane heparan and chondroitin sulfate proteoglycans (HSPGs), which are expressed by arterial smooth muscle cells (SMCs), are regulated in injured arteries, bind various growth factors and components of the extracellular matrix (ECM), and are important regulators of cell-growth factor, cell-cell, and cell-ECM interactions. While it is known that heparan sulfate glycosaminoglycans and heparin suppress injury-induced intimal thickening by inhibiting SMC migration and proliferation and by altering SMC ECM production, the role of syndecans in SMC growth and the response to arterial injury has not been defined. We have recently found that intimal thickening and medial proliferation are markedly increased in the injured carotid arteries of syndecan-1 null mice. In addition, cultured arterial SMCs from these mice express higher levels of PDGF-B mRNA and migrate and proliferate more than SMCs from wild-type mice in response to PDGF-BB, serum, EGF, FGF2, and thrombin. siRNAs for PDGF-B chain and PDGFR-beta knock down their respective targets and suppress thrombin-, PDGF-BB-, and serum-induced SMC proliferation. These findings demonstrate to us that syndecan-1 is a negative regulator of arterial SMC growth. The major goal of this proposal is to determine how syndecan-1 transcription is regulated and how syndecan-1 then controls PDGF-B induction in response to growth factors. The specific aims are: 1. To define the mechanism of syndecan-1 regulation in vitro and in vivo; 2. To define the mechanisms by which syndecan-1 inhibits thrombin-mediated induction of PDGF-B chain; and 3. To determine in structure-function studies whether the syndecan-1 ectodomain, the cytoplasmic domain, or both are required for syndecan-1 inhibition of PDGF-B induction and cell growth. The proposed studies should provide novel insights regarding syndecan-1, which will then form the basis for the development of pharmacology to prevent restenosis, a problem that affects large numbers of patients undergoing coronary stent angioplasty. PUBLIC HEALTH RELEVANCE: The proposed studies should provide novel insights regarding syndecan-1, a molecule expressed by smooth muscle cells that suppresses the formation of intimal thickening after arterial injury. These observations will then form the basis for the development of pharmacology to prevent restenosis, a problem that affects large numbers of patients undergoing coronary stent angioplasty.