Molecular profiling of pro-inflammatory HDL

促炎 HDL 的分子谱

基本信息

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
项目类别：
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

项目摘要

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和死亡的主要原因。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。根据最近对动物模型和人类样本的多项研究，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开发 i) 用于早期检测动脉粥样硬化的新型生物标志物，ii) 用于跟踪治疗方法功效的生物标志物基于 HDL 功能，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 技术与表面增强激光解吸/电离飞行时间质谱 (SELDI-TOF-MS) 相结合来促进蛋白质分析。我们已成功利用该技术，并率先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分析研究中，我们鉴定了八个蛋白核心特征（由它们的 m/z 峰表示），可用作血清生物标志物组，用于识别小鼠中的促炎 HDL。我们进一步证明血红蛋白-α、血红蛋白-β 和 XII PLA2 代表八蛋白核心特征中的三个峰。在这项拨款提案中，我们建议 i) 识别并表征区分促炎 HDL 和抗炎 HDL 的其余 5 种蛋白质，ii) 确定促炎 HDL 和抗炎 HDL 之间血红蛋白和第 XII 组 PLA2 差异的生物学基础抗炎 HDL，以及 iii) 确定新生物标志物在动脉粥样硬化小鼠模型中基于 apoA1 模拟肽的治疗中的效用和功能。动脉粥样硬化是心血管疾病发病的根本原因。了解区分促炎 HDL 和抗炎 HDL 的蛋白质谱将为动脉粥样硬化的早期检测和治疗干预提供新策略。