COBRE: OK MED RES FOUND: P5: ROLE OF PROTEOGLYCAN IN ATHEROGENESIS

COBRE：确定医学研究结果：P5：蛋白聚糖在动脉粥样硬化中的作用

• 批准号: 7610581
• 负责人: MYRON E HINSDALE
• 金额: $ 25.08万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610581
• 关键词: Anabolism; Animal Model; Apolipoprotein E; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Binding; Blood Vessels; Cells; Chondroitin Sulfates; Collagen; Computer Retrieval of Information on Scientific Projects Database; Development; Endothelial Cells; Funding; Glycosaminoglycans; Goals; Grant; Histologic; Human; Immunohistochemistry; In Vitro; Institution; Lesion; Lipoprotein Binding; Lipoproteins; Localized; Low Density Lipoprotein Receptor; Magnetic Resonance Imaging; Measures; Mediating; Modification; Mus; Pathogenesis; Pathology; Proteins; Proteoglycan; Research; Research Personnel; Resources; Role; Smooth Muscle Myocytes; Source; Standards of Weights and Measures; Structure; Testing; Transforming Growth Factor beta; United States National Institutes of Health; atherogenesis; biglycan; decorin; dermatan sulfate proteoglycan; intravital microscopy; mouse model; versican

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this proposal is to investigate the role of chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycan biosynthesis in atherogenesis. As an atherosclerotic lesion develops in the blood vessel wall, CS and DS proteoglycans biglycan, decorin, and versican accumulate. Because lipoproteins bind in vitro to proteoglycans and co-localize with them in the atherosclerotic lesion, it has been hypothesized that increased proteoglycan biosynthesis by cells in the vessel wall is atherogenic. Biglycan is a likely candidate proteoglycan for binding and retaining lipoproteins since it binds atherogenic lipoproteins in vitro, colocalizes with apolipoprotein B (apoB) and E (apoE) in human atherosclerotic lesions, and more closely colocalizes with apoB and apoE in mouse lesions than decorin. Furthermore, because biglycan has both protein and glycosaminoglycan (GAG)-mediated interactions with other proteins (e.g. collagens, lipoproteins, TGFbeta), we hypothesize that these interactions are important to the structure and development of the lesion in the vascular wall. To test these hypotheses our three aims focus on measuring and characterizing atherosclerosis in 3 animal models, In specific aim 1, we will determine whether increased biosynthesis of biglycan by endothelial cells can exaggerate the development of atherosclerosis. In specific aim 2, we will determine whether increased biosynthesis of biglycan by vascular smooth muscle cells can exaggerate the development of atherosclerosis. In specific aim 3, we will determine whether the GAG modifications of biglycan are important for atherosclerotic lesion development and structure. All three mouse models will be made atherogenic by crossing them to either low-density lipoprotein receptor deficient or apolipoprotein E deficient mice. Our objectives with these mouse models of atherosclerosis are to determine the roles increased biosynthesis and GAG modification of biglycan have in atherosclerotic lesion development and progression. In addition to standard atherosclerotic lesion analysis and extensive histologic characterization including immunohistochemistry for different collagen types and biglycan, intravital microscopy and magnetic resonance imaging will be used to characterize the vascular pathology in these mice. Overall, these proposed studies will more clearly define the role biglycan accumulation and biglycan GAG modification have in the pathogenesis of atherosclerosis.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该提案的目的是研究硫酸软骨素（CS）和硫酸皮肤菌（DS）蛋白聚糖生物合成在动脉粥样硬化中的作用。随着血管硬化病变在血管壁中发育，CS和DS蛋白聚糖大型群，Decorin和Versican会累积。因为脂蛋白在体外结合与 蛋白聚糖并与它们共定位在动脉粥样硬化病变中，已经假设血管壁中细胞增加的蛋白聚糖生物合成增加是动脉粥样硬化的。 Biglycan可能是一种用于结合和保留脂蛋白的候选蛋白聚糖，因为它在体外结合了动脉粥样硬化脂蛋白，与载脂蛋白B（APOB）和E（APOE）共定位，在人动脉粥样硬化病变中与E（APOE）进行，并且在小鼠Lesions中与apob和Apoe更紧密地共同依靠。此外，由于Biglycan同时具有蛋白质和糖胺聚糖（GAG）介导的与其他蛋白质（例如胶原蛋白，脂蛋白，TGFBETA）的相互作用，因此我们假设这些相互作用对血管壁中病变的结构和发育很重要。 为了检验这些假设，我们的三个目的集中在3种动物模型中测量和表征动脉粥样硬化的特征1，在特定的目标1中，我们将确定内皮细胞对Biglycan的生物合成增加是否会夸大动脉粥样硬化的发展。在特定的目标2中，我们将确定血管平滑肌细胞对大型群体的生物合成是否会夸大动脉粥样硬化的发展。在特定目标3中，我们将确定Biglycan的插孔修饰对于动脉粥样硬化病变的发育和结构是否重要。所有三种小鼠模型都将通过将它们跨到低密度脂蛋白受体缺乏或载脂蛋白E缺乏小鼠来制定。我们使用这些动脉粥样硬化的小鼠模型的目标是确定生物合成增加的作用，并在动脉粥样硬化病变的发育和进展中对Biglycan的堵嘴改变。除了标准的动脉粥样硬化病变分析和广泛的组织学表征外，还将使用用于不同胶原蛋白类型的免疫组织化学和大型胶原蛋白，内部显微镜和磁共振成像来表征这些小鼠的血管病理。总体而言，这些拟议的研究将更清楚地定义Biglan积累的作用，并在动脉粥样硬化的发病机理中进行大型插科打gog的修饰。