Innate Immunity, Biomarkers and Myocardial Infarction

描述（由申请人提供）： 本申请涉及挑战领域（03）生物标志物发现和验证。本申请中涵盖的特定主题是高优先级主题，标题为：03-HL-101鉴别和验证血液、血管、心脏和呼吸道功能障碍诊断和治疗反应的临床相关、可量化生物标志物。虽然缺血/再灌注损伤的确切机制仍不清楚，但抑制补体激活（例如，sCR 1或C1酯酶抑制剂），补体成分的消耗（例如，眼镜蛇毒因子）和使用遗传修饰的小鼠已经证明了补体在缺血/再灌注损伤中的重要作用。虽然最近的临床试验（例如，APEX-MI和COMPANY）对主要终点未达到统计学显著性，由于PRIMO-CABG 2试验在CABG中失败而提前结束，安慰剂组的不良反应显著减少，许多公司仍有积极的补体抑制剂项目。我们认为，抗C5 mAb（pexelizumab）临床试验失败的另一个原因是不完全了解每种补体成分的作用，也不完全了解MI中补体激活的机制。我们实验室发表的数据清楚地表明，甘露糖结合凝集素（MBL）启动补体激活，激活后，级联放大的替代途径。此外，我们证明了在Alexion临床试验中完成的C5 b-9形成的完全抑制导致动物模型中的组织损伤增加。我们开发了一种新的四点免疫测定来定量MBL途径内的补体成分，因此我们可以筛选人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果的研究领域，因为MBL 2基因的多重多态性导致10-15%的人群MBL缺乏。本申请将通过将我们的实验室研究转化为床边研究来完成我们对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测定的初步数据表明，在再灌注的前30天内死亡的MI患者中MBL水平显著较高。此外，初步数据表明，MBL水平增加与糖尿病史。本申请将确立并验证MBL作为心肌梗死溶栓治疗后发病率和死亡率增加的新型生物标志物。 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。心肌梗死的体外研究和动物模型证明MBL作为补体激活、组织炎症和损伤的引发剂的重要作用。该基金将使用已建立的生物储存库样本和数据库，确定并验证MBL和/或其活化产物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志物。

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.