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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的目的是探讨硫酸软骨素（CS）和硫酸皮肤素（DS）蛋白多糖生物合成在动脉粥样硬化形成中的作用。随着动脉粥样硬化病变在血管壁中的发展，CS和DS蛋白聚糖双糖蛋白聚糖、核心蛋白聚糖和多功能蛋白聚糖积累。因为脂蛋白在体外与 蛋白聚糖的生物合成增加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的蛋白聚糖生物合成增加是致动脉粥样硬化的。双糖蛋白聚糖是用于结合和保留脂蛋白的可能的候选蛋白聚糖，因为它在体外结合致动脉粥样硬化脂蛋白，在人动脉粥样硬化病变中与载脂蛋白B（apoB）和E（apoE）共定位，并且在小鼠病变中与apoB和apoE比核心蛋白聚糖更紧密地共定位。此外，由于双糖链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、TGF β）的相互作用，我们假设这些相互作用对血管壁中病变的结构和发展是重要的。 为了验证这些假设，我们的三个目标集中在测量和表征3种动物模型中的动脉粥样硬化。在具体目标1中，我们将确定内皮细胞生物合成双糖链蛋白聚糖的增加是否会加剧动脉粥样硬化的发展。在具体目标2中，我们将确定血管平滑肌细胞生物合成双糖链蛋白聚糖的增加是否会加剧动脉粥样硬化的发展。在具体目标3中，我们将确定双糖链蛋白聚糖的GAG修饰对于动脉粥样硬化病变的发展和结构是否重要。所有三种小鼠模型将通过将它们与低密度脂蛋白受体缺陷或载脂蛋白E缺陷小鼠杂交来产生致动脉粥样硬化性。我们的目的是用这些小鼠动脉粥样硬化模型来确定双糖链蛋白聚糖的生物合成增加和GAG修饰在动脉粥样硬化病变发展和进展中的作用。除了标准动脉粥样硬化病变分析和广泛的组织学表征（包括不同胶原类型和双糖链蛋白聚糖的免疫组织化学）外，还将使用活体显微镜和磁共振成像来表征这些小鼠的血管病理学。总之，这些拟议的研究将更清楚地定义双糖链聚糖积累和双糖链聚糖GAG修饰在动脉粥样硬化发病机制中的作用。