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：
8118086
负责人：
ALEXANDER W CLOWES
金额：
$ 41.95万
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/8118086
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 PDGFRB gene Pathway interactions Patients Pharmacology Platelet-Derived Growth Factor 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）：syndecans（Syndecans -1，-2，-3和-4）是跨膜肝素和硫酸软骨素蛋白聚糖（HSPG），由动脉平滑肌细胞（SMC）表达，在受伤的动脉中受伤的生长因子和组合因子（coe）的各种因素和构成因子（coe）的各种因素和兼容性圈子（SMC）的各种因素和兼容性的圈子的含量（细胞增长因子，细胞细胞和细胞ECM相互作用。众所周知，硫酸乙酰肝素糖胺聚糖和肝素通过抑制SMC的迁移和增殖以及改变SMC ECM的产生，抑制损伤诱导的内膜增厚，而Syndecans在SMC生长中的作用以及对动脉损伤的反应尚未定义。我们最近发现，在syndecan-1 null小鼠的受伤的颈动脉中，内膜增厚和内侧增殖明显增加。此外，来自这些小鼠的培养的动脉SMC表达了较高水平的PDGF-B mRNA，并响应于PDGF-BB，血清，EGF，FGF2和凝血酶来迁移和增殖。 PDGF-B链和PDGFR-BETA的siRNA击倒了各自的靶标，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了Syndecan-1是动脉SMC生长的负调节剂。该提案的主要目的是确定如何调节Syndecan-1转录以及Syndecan-1如何控制PDGF-B诱导对生长因子的响应。具体目的是：1。定义体外和体内调节syndecan-1的机理； 2。定义syndecan-1抑制凝血酶介导的PDGF-B链诱导的机制； 3。在结构功能中确定syndecan-1胞外域，细胞质结构域或同时抑制PDGF-B诱导和细胞生长所必需的。拟议的研究应提供有关Syndecan-1的新见解，然后这将构成预防再狭窄的药理学的基础，这一问题影响了大量接受冠状动脉支架血管成形术的患者。公共卫生相关性：拟议的研究应提供有关Syndecan-1的新见解，Syndecan-1是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。然后，这些观察结果将构成预防再狭窄的药理学发展的基础，这是影响大量接受冠状动脉支架血管成形术的患者的问题。