Mannose binding lectin and outcomes following CABG

甘露糖结合凝集素和冠状动脉搭桥术后的结果

• 批准号: 7587876
• 负责人: Simon C Body
• 金额: $ 25.31万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587876
• 关键词: American; Animal Model; Animals; Antibodies; Basic Science; Biological Assay; Blood; Blood Vessels; Blood specimen; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cardiovascular Diseases; Caring; Cessation of life; Chromosomes; Classical Complement Pathway; Clinical; Clinical Sciences; Clinical Trials; Coagulation Process; Complement; Complement 1 Inactivators; Complement 3b; Complement 4b; Complement Activation; Coronary; Coronary Artery Bypass; Creatine Kinase; Data; Databases; Deposition; Development; Exposure to; Fluorochrome; Functional disorder; Funding; Genes; Genetic; Genetic Variation; Genomics; Haplotypes; Heart; Hospitals; Human; Immune; Immunoassay; Immunoglobulin M; Individual; Infarction; Inflammation; Inflammatory; Injury; Institutes; Ischemia; Knockout Mice; Laboratories; Lead; Lectin; Link; Mannose Binding Lectin; Mannose-Binding Lectins; Measures; Mediating; Molecular Genetics; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Percutaneous Transluminal Coronary Angioplasty; Perioperative; Phenotype; Physiology; Play; Postoperative Period; Proteins; Reperfusion Injury; Reperfusion Therapy; Resources; Risk; Role; Sampling; Serum; Severities; Stratification; Surface; Texas; Thrombolytic Therapy; Time; Tissues; Trauma; Troponin I; Variant; Vascular Diseases; Woman; activation product; cobra venom factor; complement pathway; cost; gastrointestinal; human disease; improved; insight; mortality; natural hypothermia; novel; programs; public health relevance; repository; restoration; socioeconomics

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.

描述（由申请人提供）：冠状血管疾病可导致心肌梗塞。虽然护理标准的提高大大改善了梗死后的发病率和死亡率，但现在人们普遍认为，在成功的溶栓治疗、经皮冠状动脉成形术和体外循环（CPB）冠状动脉旁路移植术（CABG）后会发生缺血/再灌注（I/R）损伤。尽管众所周知，I/R、炎症和凝血障碍会导致围手术期不良后果（例如表型），但观察到的这些结果的严重程度在个体之间存在显着差异。一种可能的解释是介导不良围手术期后果的生物途径的遗传变异。包括我们自己在内的多个小组最近的基础科学研究表明，补体在缺血再灌注损伤中发挥着重要作用。我们已经证明，抑制凝集素补体途径的甘露糖结合凝集素（MBL）依赖性部分在心肌缺血动物模型再灌注后的炎症、功能障碍和损伤中发挥重要作用。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型荧光染料连接免疫测定 (FLISA)，以测量凝集素补体途径对人血清中 C3 裂解水平的功能方面。来自 CABG 基因组计划的初步单倍型数据表明，高表达 MBL2“LYQA 分泌者”单倍型是 CABG 手术后心肌梗死的独立预测因子。在本申请中，我们将使用 CABG 基因组计划数据库和样本存储库，在 CABG 环境中结合基因组 (MBL2) 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 MBL2 基因内的遗传变异和围手术期血清 MBL 水平将成为 CABG 术后 CPB 心肌损伤的预测指标。该提案产生的数据不仅将进一步明确 MBL 和 LCP 在心肌损伤中的作用，还将深入了解导致个体在心脏手术后发生围手术期发病的遗传和分子机制。此外，成功完成这些具体目标可能会改善围手术期风险分层、资源利用以及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：心血管疾病造成的死亡仍然是美国人的第一大杀手。人类和动物研究的最新科学发现表明，已知先天免疫分子（例如甘露糖结合凝集素，MBL2）的遗传变异性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新型且经过验证的免疫测定法，我们将研究 MBL2 基因内的遗传变异和围手术期 MBL2 血清浓度（及其下游激活产物 C4b 和 C3b），以使用 CABG 基因组计划数据库和样本库预测 CABG 后发生的心肌损伤。