Innate Immunity, Biomarkers and Myocardial Infarction

描述(由申请人提供)： 本申请涉及挑战领域(03)生物标记物发现和验证。本申请中涉及的特定主题是高优先级主题：03-HL-101识别和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可量化的生物标记物。虽然缺血/再灌注损伤的确切机制尚不清楚，但抑制补体激活(如sCR1或C1酯酶抑制剂)、耗尽补体成分(如眼镜蛇蛇毒因子)以及使用转基因小鼠已显示补体在缺血/再灌注损伤中的重要作用。虽然最近的临床试验(如APEX-MI和Compline)没有达到主要终点的统计学意义，由于在CABG中的Primo-CABG2试验失败而提前结束，并显著减少了安慰剂组的不良反应，但许多公司仍然有积极的补体抑制剂计划。我们认为，抗C5单抗(Pexelizumab)临床试验失败的另一个原因是不完全了解每个补体成分的作用，也不完全了解补体在MI中的激活机制。我们实验室公布的数据清楚地表明，甘露糖结合凝集素(MBL)启动补体激活，激活后，级联被替代途径放大。此外，我们还证明，在Alexion临床试验中，完全抑制C5b-9的形成会导致动物模型中组织损伤的加剧。我们开发了一种新的四点免疫分析方法来定量MBL途径中的补体成分，这样我们就可以筛选人类血清库和数据库来评估MBL在人类疾病中的作用。我们相信这将是一个富有成效的研究领域，因为MBL2基因的多重多态导致10-15%的人群中存在MBL缺陷。这一应用将通过将我们的实验室研究转移到床边来完成我们对MBL在心肌缺血中的作用的研究。在接受心肌梗死溶栓治疗的患者中使用MBL检测的初步数据显示，在再灌注前30天内死亡的MI患者的MBL水平显著高于其他患者。此外，初步数据显示，有糖尿病病史的患者MBL水平升高。这项应用将建立和验证MBL作为心肌梗死溶栓治疗后增加发病率和死亡率的新的生物标志物。 公共卫生相关性：心血管疾病死亡仍然是美国人的头号杀手。体外研究和心肌梗死动物模型表明，MBL作为补体激活、组织炎症和损伤的起始者具有重要作用。这笔赠款将利用已建立的生物库样本和数据库来确定和验证MBL和/或其激活产品是否是心肌梗死溶栓治疗后心功能障碍和死亡率的生物标记物。

DESCRIPTION (provided by applicant): This application addresses the Challenge Area (03) Biomarker Discovery and Validation. The specific topic covered in this application is the high priority topic entitled: 03-HL-101 Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. While the exact mechanisms of ischemia/reperfusion injury remain unclear, inhibition of complement activation (e.g., sCR1 or C1 esterase inhibitor), depletion of complement components (e.g., cobra venom factor) and the use of genetically modified mice have demonstrated an important role of complement in ischemia/reperfusion injury. While recent clinical trials (e.g., APEX-MI and COMPLY) did not reach statistical significance for the primary endpoint, ended early because of the failed PRIMO-CABG2 trial in CABG, and significantly reduced adverse affects in the placebo group, many companies still have active complement inhibitor programs. We believe another reason for the failed clinical trial with the anti-C5 mAb (pexelizumab) was a result of not completely knowing the roles of each of the complement components, nor the mechanisms of complement activation in MI. Published data from our laboratory clearly demonstrate that mannose-binding lectin (MBL) initiates complement activation and, after activation, the cascade is amplified by the alternative pathway. Further, we demonstrated that complete inhibition of C5b-9 formation, which was done in the Alexion clinical trials, leads to augmented tissue injury in animal models. We developed a novel four point immunoassay to quantify the complement components within the MBL pathway so we can screen human sera repositories and databases to evaluate the role of MBL in human disease. We believe this will be a fruitful area of investigation, as multiple polymorphisms in the MBL2 gene lead to MBL deficiency in 10-15% of the population. This application will complete our investigations into the role of MBL in myocardial ischemia by translating our bench studies to the bedside. Preliminary data using the MBL assay in patients undergoing thrombolytic therapy for myocardial infarction demonstrate significantly higher MBL levels in MI patients that have died within the first 30 days of reperfusion. Further, preliminary data demonstrate increased MBL levels with a history of diabetes. This application will establish and validate MBL as a novel biomarker for increased morbidity and mortality following thrombolytic therapy for myocardial infarction. Public Health Relevance: Death from cardiovascular disease remains the number one killer of Americans. In vitro studies and animal models of myocardial infarction demonstrate a significant role for MBL as the initiator of complement activation, tissue inflammation and injury. This grant will establish and validate whether MBL and/or its activation products are biomarkers for cardiac dysfunction and mortality following thrombolytic therapy for myocardial infarction using established biologic repository samples and database.