Molecular profiling of pro-inflammatory HDL

描述（由申请人提供）：在西方社会，动脉粥样硬化是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）胆固醇是冠心病引起临床事件风险的良好流行病学预测因子。基于最近在动物模型和人类样本中的许多研究，很明显HDL功能的抗炎或促炎性质而不是HDL胆固醇水平是动脉粥样硬化存在或不存在的敏感指标。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，并且此类蛋白质的鉴定将导致i）用于早期检测动脉粥样硬化的新生物标志物的开发，ii）用于遵循基于HDL功能的治疗方法的功效的生物标志物，和iii）用于动脉粥样硬化的治疗干预的新策略。我们的实验室利用蛋白质芯片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，并首次报告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的初步血清蛋白质谱研究中，我们鉴定了八种蛋白质核心特征（由其m/z峰表示），其可用作血清生物标志物组以鉴定小鼠中的促炎性HDL。我们进一步证明了血红蛋白-α、血红蛋白-β和第XII族PLA 2代表八蛋白核心特征中的三个峰。在该资助提案中，我们建议i）鉴定和表征区分促炎性HDL和抗炎性HDL的其余五种蛋白质，ii）确定促炎性HDL和抗炎性HDL之间血红蛋白和第XII组PLA 2差异的生物学基础，以及iii）确定新生物标志物在基于apoA 1模拟肽的治疗中在动脉粥样硬化小鼠模型中的效用和功能。 动脉粥样硬化是心血管疾病发病的根本原因。区分促炎HDL和抗炎HDL的蛋白质谱的知识将为动脉粥样硬化的早期检测以及治疗干预提供新的策略。

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.