Molecular profiling of pro-inflammatory HDL

描述(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(高密度脂蛋白)胆固醇和低密度脂蛋白(低密度脂蛋白)胆固醇是冠心病临床事件风险的良好流行病学预测指标。根据最近在动物模型和人类样本中的一些研究，很明显，高密度脂蛋白功能的抗炎或促炎性质而不是高密度脂蛋白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：我们假设与高密度脂蛋白相关的特定蛋白质是其炎症特性的功能决定因素，对这些蛋白质的识别将导致以下方面的发展：1)用于动脉粥样硬化早期检测的新生物标记物，2)基于高密度脂蛋白功能的治疗方法有效性跟踪的生物标记物，以及3)动脉粥样硬化治疗干预的新策略。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/电离飞行时间质谱仪(SELDI-TOF-MS)来促进蛋白质图谱的建立。我们已经成功地利用了这项技术，并首次报告了用于卵巢癌早期检测的三组生物标志物的鉴定。在使用SELDI-TOF-MS进行的初步血清蛋白质谱研究中，我们确定了一个八个蛋白质核心特征(由它们的m/z峰表示)，该特征可用作鉴定小鼠促炎症高密度脂蛋白的血清生物标志物。我们进一步证明，血红蛋白-α、血红蛋白-β和XII-PLA2组代表了八个蛋白质核心特征中的三个峰。在这项拨款提案中，我们建议：i)鉴定和表征其余五种区分促炎和抗炎高密度脂蛋白的蛋白质；ii)确定Hb和XII组PLA2、促炎和抗炎高密度脂蛋白之间差异的生物学基础；iii)确定新的生物标志物在载脂蛋白A1模拟多肽治疗动脉粥样硬化小鼠模型中的实用性和功能。 动脉粥样硬化是心血管疾病发病的潜在原因。区分致炎高密度脂蛋白和抗炎高密度脂蛋白的蛋白质谱知识将为动脉粥样硬化的早期发现和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.