Detection of Oxidized LDL in Plasma

描述（由申请方提供）：由于60%的血浆胆固醇与低密度脂蛋白（LDL）相关，因此降低LDL c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Meta分析一致表明，虽然临床事件的风险随着LDL c降低而降低，但动脉粥样硬化的进展并未停止。尽管LDLc已达到目标水平，但许多患者仍继续发生临床事件，包括死亡。根据动脉粥样硬化的氧化假说，天然LDL不是致动脉粥样硬化的。另一方面，已经被氧化修饰的LDL颗粒可以被巨噬细胞贪婪地摄取，导致泡沫细胞和斑块不稳定性的形成。我们已经开发了许多特异性和高灵敏度的单克隆抗体对磺基丙氨酸（氧化形式半胱氨酸），这是一种最常见的形式，自然发生的蛋白质氧化。使用K2F1.6克隆（保藏于ATCC PTA-897，美国专利6，953，666 B1）的初步数据表明，与健康对照相比，在高风险个体中可以检测到广泛的阳性信号。这项SBIR I期研究的目的是证明这种氧化标志物在有和无心血管疾病（包括有记录的冠状动脉疾病）的大型患者队列中的临床意义。将提供来自三个患者队列的样本（1）具有和不具有CAD的自由生活个体，其特征为病史和内皮功能障碍（肱动脉血流介导的扩张），（2）NIH资助的退伍军人双心研究的参与者，其临床特征为MRI和内皮功能障碍，（3）2型糖尿病伴或不伴CAD的退伍军人，已接受LDLc目标治疗。这将是一项前瞻性、巢式病例对照、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过传统的风险因素。使用基于识别氧化半胱氨酸部分的独特单克隆抗体的受专利保护的ELISA测定，我们建议定义该氧化表位在三个独立的受试者队列中的分布，包括健康对照组、2型糖尿病患者和有记录的CAD患者。

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.