Detection of Oxidized LDL in Plasma

血浆中氧化 LDL 的检测

• 批准号: 7745617
• 负责人: Kenneth Dombrowski
• 金额: $ 10万
• 依托单位: CARDIOVASCULAR SPECIALTY LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745617
• 关键词: Angiography; Atherosclerosis; Award; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Cholesterol; Clinical; Clinical Trials; Coronary Arteriosclerosis; Cysteic Acid; Cysteine; Data; Deposition; Detection; Diabetes Mellitus; Diagnostic; Dilatation - action; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Epitopes; Event; Exhibits; Foam Cells; Framingham Heart Study; Functional disorder; Funding; Future; Goals; Hand; Heart; Individual; Inflammation; Intervention; Intervention Trial; Laboratories; Legal patent; Licensing; Life; Low-Density Lipoproteins; Magnetic Resonance Imaging; Mediating; Medical History; Meta-Analysis; Monoclonal Antibodies; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Oxidative Stress; Participant; Patients; Phase; Plasma; Prevention; Proteins; Research; Research Design; Residual state; Risk; Risk Factors; Signal Transduction; Single-Blind Study; Small Business Innovation Research Grant; Specimen; Symptoms; Technology; Therapeutic; Twin Multiple Birth; United States National Institutes of Health; Universities; Veterans; Woman; active method; base; brachial artery; case control; clinically significant; cohort; high risk; indexing; macrophage; medical specialties; men; mortality; oxidation; oxidized low density lipoprotein; particle; prospective; public health relevance

DESCRIPTION (provided by applicant): With 60% of plasma cholesterol being associated with low-density lipoproteins (LDL), reduction in LDLc is one of the primary targets for intervention to reduce cardiovascular disease. However, meta- analyses of available clinical trials have consistently demonstrated that, while the risk for clinical event is reduced with LDLc reduction, the progression of atherosclerosis is not stopped. Many patients continue to have clinical events, including death, in spite of having reached target levels for LDLc. According to the oxidation hypothesis of atherosclerosis, native LDL is not atherogenic. LDL particles that have been oxidatively modified, on the other hand, can be avidly taken up by macrophages leading to the formation of foam cells and plaque instability. We have developed a number of specific and highly sensitive monoclonal antibodies against cysteic acid (oxidized form cysteine), which is one of the most common forms of naturally occurring protein oxidation. Preliminary data using the K2F1.6 clone (deposited with the ATCC PTA-897, US patent 6,953,666B1) indicates that a wide range of positive signals can be detected in high-risk individuals as compared to healthy controls. The objective of this SBIR Phase 1 is to demonstrate the clinical significance of this oxidative marker in a large cohort of patients with and without cardiovascular disease, including documented coronary artery disease. Specimen from three cohorts of patients will be available (1) free-living individuals with and without CAD as characterized from medical history and endothelial dysfunction (brachial artery flow-mediated dilatation), (2) participants in the NIH funded Veterans Twin Heart Study characterized clinically by MRI and endothelial dysfunction, (3) veterans with type 2 diabetes mellitus with and without concomitant CAD who have been treated to LDLc goal. This will be a prospective, nested case-control single-blind study design. PUBLIC HEALTH RELEVANCE: Elevated plasma levels of oxidized LDL may contribute to the risk for future cardiovascular events beyond the traditional risk factors. Using a patent-protected ELISA assay based on a unique monoclonal antibody that recognizes an oxidized cysteine moiety, we propose to define the distribution of this oxidized epitope in three independent cohorts of subjects including healthy controls, patients with type 2 diabetes mellitus and patients with documented CAD.

描述（由申请人提供）：60%的血浆胆固醇与低密度脂蛋白（LDL）相关，降低低密度脂蛋白是减少心血管疾病干预的主要目标之一。然而，现有临床试验的荟萃分析一致表明，虽然临床事件的风险随着ldl的降低而降低，但动脉粥样硬化的进展并没有停止。许多患者尽管已达到ldl的目标水平，但仍出现临床事件，包括死亡。根据动脉粥样硬化的氧化假说，天然LDL不会导致动脉粥样硬化。另一方面，被氧化修饰的LDL颗粒可以被巨噬细胞大量吸收，导致泡沫细胞的形成和斑块的不稳定。我们已经开发了一些针对半胱氨酸（半胱氨酸氧化形式）的特异性和高度敏感的单克隆抗体，半胱氨酸是自然发生的蛋白质氧化的最常见形式之一。使用K2F1.6克隆（提交给ATCC PTA-897，美国专利6,953,666B1）的初步数据表明，与健康对照相比，高危人群中可以检测到广泛的阳性信号。该SBIR一期研究的目的是证明这种氧化标志物在一大群有或无心血管疾病的患者（包括有记录的冠状动脉疾病）中的临床意义。来自三组患者的样本将被提供(1)有和没有CAD的自由生活个体，其特征是病史和内皮功能障碍（肱动脉血流介导的扩张），(2)美国国立卫生研究院资助的退伍军人双心研究的参与者，其临床特征是MRI和内皮功能障碍，(3)患有2型糖尿病的退伍军人，伴有或不伴有CAD，并已治疗到LDLc目标。这将是一项前瞻性、嵌套病例对照的单盲研究设计。公共卫生相关性：血浆氧化低密度脂蛋白水平升高可能导致未来心血管事件的风险超出传统的危险因素。利用专利保护的ELISA检测，基于一种独特的单克隆抗体识别氧化半胱氨酸片段，我们提出确定该氧化表位在三个独立队列中的分布，包括健康对照、2型糖尿病患者和有记录的CAD患者。