Molecular profiling of pro-inflammatory HDL

促炎 HDL 的分子谱

• 批准号: 7392286
• 负责人: SRINIVASA T. Reddy
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392286
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Applications Grants; Atherosclerosis; Biological; Biological Assay; Biological Markers; Cardiovascular Diseases; Clinical; Core Protein; Coronary Arteriosclerosis; Coupled; Development; Diet; Early Diagnosis; Enzymes; Event; Generations; Haptoglobins; Hemoglobin; Hemopexin; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Immunoprecipitation; Inbred Strains Mice; Inflammatory; Knockout Mice; Knowledge; LDL Cholesterol Lipoproteins; Laboratories; Link; Mass Spectrum Analysis; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Nature; Numbers; Peptide Mapping; Peptides; Phospholipase A2; Play; Property; Proteins; Reporting; Risk; Role; Sampling; Screening for Ovarian Cancer; Serum; Serum Proteins; Set protein; Societies; Technology; Therapeutic Intervention; Time; Treatment Efficacy; Western Blotting; base; mimetics; mortality; mouse model; novel; research study; surface enhanced laser desorption ionization

DESCRIPTION (provided by applicant): Atherosclerosis is the leading cause of morbidity and mortality in the Western society. High density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol are good epidemiological predictors of risk for clinical events caused by coronary artery disease. Based on a number of recent studies in both animal models and human samples it is clear that the anti- or pro-inflammatory nature of HDL function and not HDL cholesterol levels is a sensitive indicator of the presence or absence of atherosclerosis. Hypothesis: We hypothesize that specific proteins associated with HDL are the functional determinants of its inflammatory properties and identification of such proteins will result in the development of i) novel biomarkers for the early detection of atherosclerosis, ii) biomarkers for following the efficacy of therapeutic approaches that are based on HDL function, and iii) new strategies for therapeutic interventions of atherosclerosis. Our laboratory utilizes ProteinChip technology coupled with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to facilitate protein profiling. We have successfully utilized the technology and were the first to report the identification of three panels of biomarkers for the early detection of ovarian cancer. In preliminary serum protein profiling studies using SELDI-TOF-MS, we identified an eight-protein core signature (represented by their m/z peaks) that can be used as a serum biomarker panel for identifying pro-inflammatory HDL in mice. We further demonstrated that Hemoglobin-alpha, Hemoglobin-beta, and group XII PLA2 represent three of the peaks in the eight-protein core signature. In this grant proposal, we propose to i) identify and characterize the remaining five proteins that distinguish pro-inflammatory HDL from anti-inflammatory HDL, ii) determine the biological basis for the differences in Hemoglobin and group XII PLA2, between pro-inflammatory and anti-inflammatory HDL, and iii) determine the utility and function of the new biomarkers in apoA1 mimetic peptide based therapy in mouse models of atherosclerosis. Atherosclerosis is an underlying cause for onset of cardiovascular diseases. The knowledge of protein profiles that distinguish pro-inflammatory HDL from anti-inflammatory HDL will provide will provide new strategies for early detection as well as therapeutic intervention of atherosclerosis.

描述（由申请人提供）：动脉粥样硬化是西方社会发病率和死亡率的主要原因。高密度脂蛋白（HDL）胆固醇和低密度脂蛋白（LDL）胆固醇是冠状动脉疾病引起的临床事件风险的良好流行病学预测因子。基于最近对动物模型和人类样本的大量研究，很明显，高密度脂蛋白的抗炎或促炎性质的功能，而不是高密度脂蛋白胆固醇水平是动脉粥样硬化存在与否的敏感指标。假设：我们假设与HDL相关的特定蛋白质是其炎症特性的功能决定因素，这些蛋白质的鉴定将导致i)用于动脉粥样硬化早期检测的新型生物标志物的发展，ii)基于HDL功能的治疗方法疗效的生物标志物，以及iii)动脉粥样硬化治疗干预的新策略。我们的实验室利用ProteinChip技术结合表面增强激光解吸/电离飞行时间质谱（SELDI-TOF-MS）来促进蛋白质分析。我们已经成功地利用了这项技术，并首次报道了三组用于卵巢癌早期检测的生物标志物的鉴定。在使用SELDI-TOF-MS进行的初步血清蛋白分析研究中，我们确定了一个8蛋白核心特征（由它们的m/z峰表示），可以用作鉴定小鼠中促炎HDL的血清生物标志物面板。我们进一步证明，血红蛋白- α，血红蛋白- β和XII PLA2组代表八个蛋白核心特征中的三个峰。在这项拨款申请中，我们建议i)鉴定和表征区分促炎HDL和抗炎HDL的其余五种蛋白质，ii)确定促炎和抗炎HDL之间血红蛋白和XII PLA2组差异的生物学基础，以及iii)确定新的生物标志物在apoA1模拟肽治疗小鼠动脉粥样硬化模型中的效用和功能。