Mannose binding lectin and outcomes following CABG

描述（由申请人提供）：冠状血管疾病可导致心肌梗死。尽管提高的护理标准大大改善了梗死后的发病率和死亡率，但现在广泛接受的是，在成功的溶栓治疗、经皮腔内冠状动脉成形术和冠状动脉旁路移植术（CABG）和心肺转流（CPB）后会发生缺血/再灌注（I/R）损伤。尽管I/R、炎症和凝血障碍已知会导致围手术期不良结局（例如，表型），观察到的这些结果的严重程度在个体之间显著不同。一种可能的解释是介导不良围手术期结果的生物学途径中的遗传变异性。包括我们自己在内的几个研究小组最近的基础科学研究表明，补体在I/R损伤中起着重要作用。我们已经表明，抑制甘露糖结合凝集素（MBL）依赖的凝集素补体途径的一部分起着重要的作用，在心肌缺血的动物模型再灌注后的炎症，功能障碍和损伤。为了评估凝集素补体途径（LCP）在人类疾病中的作用，我们开发并验证了一种新的荧光染料连接免疫测定法（弗里萨），以测量人血清中凝集素补体途径的功能方面的C3裂解水平。来自CABG基因组计划的初步单倍型数据表明，高表达MBL 2“LYQA分泌”单倍型是CABG手术后心肌梗死的独立预测因子。在本申请中，我们将通过使用CABG基因组计划数据库和样本库在CABG的设置中组合基因组（MBL 2）和表型（MBL浓度）数据来扩展我们的基础和临床科学发现。我们假设MBL 2基因内的遗传变异和围手术期血清MBL水平将是CPB CABG手术后心肌损伤的预测指标。从这个提议中产生的数据不仅将进一步确定MBL和LCP在心肌损伤中的作用，而且还将提供对心脏手术后使个体易于围手术期发病的遗传和分子机制的深入了解。此外，这些特定目标的成功完成可能随后导致改善围手术期风险分层，资源利用和开发用于资助临床试验的新型抗补体疗法。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。最近来自人类和动物研究的科学发现已经证明，已知的先天免疫分子（例如，甘露糖结合凝集素，MBL 2）和该蛋白的血清浓度分别是冠状动脉旁路移植术（CABG）和心肌缺血/再灌注后心肌损伤的独立预测因子。使用我们实验室最近开发的一种新的经验证的免疫测定法，我们将研究MBL 2基因内的遗传变异和围手术期MBL 2血清浓度（以及其下游活化产物C4 b和C3 b），以预测CABG后发生的心肌损伤，使用CABG基因组学程序数据库和样本库。

DESCRIPTION (provided by applicant): Coronary vascular disease can lead to myocardial infarction. While increased standards of care have greatly improved morbidity and mortality following infarction, it is now widely accepted that ischemia/reperfusion (I/R) injury occurs following successful thrombolytic therapy, percutaneous transluminal coronary angioplasty and coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Although I/R, inflammation and coagulation disturbances are known to contribute to perioperative adverse outcomes (e.g., the phenotypes), the observed severity of these outcomes differs significantly amongst individuals One possible explanation is genetic variability in the biologic pathways that mediate adverse perioperative outcomes. Recent basic science studies from several groups, including our own, have shown that complement plays an important role in I/R injury. We have shown that inhibition of the mannose-binding lectin (MBL)-dependent portion of the lectin complement pathway plays an important role in the inflammation, dysfunction and injury following reperfusion in animal models of myocardial ischemia. In order to evaluate the role of the lectin complement pathway (LCP) in human diseases, we developed and validated a novel fluorochrome-linked immunoassay (FLISA) to measure the functional aspects of the lectin complement pathway to the level of C3 cleavage in human sera. Preliminary haplotype data from the CABG Genomics Program demonstrate that the high expressor MBL2 "LYQA secretor" haplotype is an independent predictor of postoperative myocardial infarction following CABG surgery. In the present application, we will extend our basic and clinical science findings by combining genomic (MBL2) and phenotypic (MBL concentration) data in the setting of CABG using the CABG Genomic Program database and sample repository. We hypothesize that genetic variation within the MBL2 gene and perioperative serum MBL levels will be predictive indicators of myocardial injury after CABG surgery with CPB. Data generated from this proposal will not only further define the role of MBL and the LCP in myocardial injury, but will also provide insight into genetic and molecular mechanisms that predispose individuals to perioperative morbidity following cardiac surgery. Furthermore, successful completion of these specific aims may subsequently lead to improved perioperative risk stratification, resource utilization and the development of novel anti-complement therapies to be used in a funded clinical trial. PUBLIC HEALTH RELEVANCE: Death from cardiovascular disease remains the number one killer of Americans. Recent scientific findings from human and animal studies have demonstrated that genetic variability of a known innate immune molecule (e.g., mannose binding lectin, MBL2) and the serum concentration of this protein are independent predictors of myocardial injury following coronary artery bypass grafting (CABG) and myocardial ischemia/reperfusion, respectively. Using a novel and validated immunoassay that was recently developed in our laboratory, we will investigate the genetic variation within the MBL2 gene and perioperative MBL2 serum concentration (as well as its downstream activation products, C4b and C3b) in predicting the myocardial injury that occurs following CABG using the CABG Genomics Program database and sample repository.