Syndecan-1 and the Arterial Response to Injury

Syndecan-1 和动脉对损伤的反应

基本信息

批准号：
7982926
负责人：
ALEXANDER W CLOWES
金额：
$ 43.1万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7982926
关键词：
Affect Angioplasty Arterial Injury Arteries Binding Blood Vessels Carotid Arteries Cell Proliferation Cells Chondroitin Sulfate Proteoglycan Coronary Cytoplasmic Tail Data Development EGF gene Extracellular Matrix FGF2 gene Genetic Transcription Goals Growth Factor Heparin Heparitin Sulfate In Vitro Individual Injury Knockout Mice Medial Mediating Messenger RNA Mus PDGF inhibition Pathway interactions Patients Pharmacology Platelet-Derived Growth Factor beta Receptor Production Proliferating Proto-Oncogene Proteins c-sis Regulation Role SRC gene Serum Signal Pathway Signaling Molecule Smooth Muscle Myocytes Stents Structure Thrombin Time Transmembrane Domain Ubiquitin Wild Type Mouse autocrine base cell growth cell motility in vivo injured insight intimal medial thickening knock-down mutant novel platelet-derived growth factor BB polysulfated glycosaminoglycan prevent public health relevance response response to injury restenosis rho syndecan ubiquitin-protein ligase

项目摘要

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.

描述（由申请人提供）： Syndecan（syndecans-1、-2、-3 和 -4）是跨膜类肝素和硫酸软骨素蛋白聚糖 (HSPG)，由动脉平滑肌细胞 (SMC) 表达，在损伤中受到调节动脉，结合各种生长因子和细胞外基质 (ECM) 成分，是细胞生长因子、细胞间和细胞间的重要调节剂。细胞-ECM 相互作用。虽然已知硫酸乙酰肝素糖胺聚糖和肝素通过抑制 SMC 迁移和增殖以及改变 SMC ECM 产生来抑制损伤引起的内膜增厚，但多聚糖在 SMC 生长和对动脉损伤反应中的作用尚未明确。我们最近发现syndecan-1缺失小鼠受损颈动脉的内膜增厚和内侧增殖显着增加。此外，来自这些小鼠的培养动脉 SMC 表达更高水平的 PDGF-B mRNA，并且响应 PDGF-BB、血清、EGF、FGF2 和凝血酶，比来自野生型小鼠的 SMC 迁移和增殖更多。 PDGF-B 链和 PDGFR-β 的 siRNA 敲低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 转录如何调节以及 syndecan-1 如何控制 PDGF-B 诱导以响应生长因子。具体目标是： 1. 明确syndecan-1体外和体内调控机制； 2. 明确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 syndecan-1 胞外域、细胞质结构域或两者是否是 syndecan-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开发的基础，再狭窄是影响大量接受冠状动脉支架血管成形术的患者的问题。公共健康相关性：拟议的研究应提供有关 syndecan-1 的新见解，syndecan-1 是一种由平滑肌细胞表达的分子，可抑制动脉损伤后内膜增厚的形成。这些观察结果将成为预防再狭窄的药理学发展的基础，再狭窄是影响大量接受冠状动脉支架血管成形术的患者的问题。