Charakterisierung der MBL (mannose binding lectin)-abhängigen Aktivierungen des Komplementsystems bei der myokardialen Ischämie- und Reperfusion (MI/R), der Rolle von C1q bei MI/R sowie Charakterisierung der Mechanismen MBL-abhängiger myokardialer Schädig

心肌缺血再灌注(MI/R)是血管外科和心肌梗死中常见的临床问题。补体激活在与MI/R相关的局部和可能的远程组织损伤中起着重要作用。我们实验室最近的证据表明，在体内阻断甘露糖结合凝集素(MBL)可以阻止补体的沉积和激活，从而显著减少MI/R后的损伤和炎症基因的表达。利用缺乏C1q(经典途径抑制)或MBL(凝集素途径抑制)或两者下游效应蛋白的小鼠，我建议识别实验性MI/R后导致组织破坏的事件。在这个建议中，我将研究MBL与C1q(即l凝集素与经典途径)在MI/R后的作用。我假设MI/R后不可逆转的心脏损伤依赖于MBL和凝集素补体途径的激活。其具体目的如下：1)研究MBL依赖的补体激活在MI/R损伤启动中的作用，并进一步评价C1q在MI/R损伤中的作用；2)确定MI/R后MBL依赖的损伤机制。

Myocardial ischemia-reperfusion (MI/R) is a common clinical problem in the settings of vascular surgery and myocardial infarction. Complement activation plays an important role in local, and likely remote, tissue injury associated with MI/R. Recent evidence from our laboratory shows that blockade of mannose binding lectin (MBL) in vivo prevents deposition and activation of complement resulting in significantly reduced injury and attenduated inflammatory gene expression following MI/R 1-3. Using mice deficient in either C1q (inhibition of the classical pathway) or MBL (inhibition of the lectin pathway), or effector proteins downstream of both, I propose to identify the events leading to tissue destruction following experimental MI/R. In this proposal, I will investigate the role of MBL vs C1q (i.e.l lectin vs. classical pathway) following MI/R. I hypothesize that irreversible cardiac damage following MI/R is dependent on MBL and lectin complement pathway activation. The specific aims are as follows: 1) Characterize MBl-dependent complement activation in the initation of MI/R injury, and additionally evaluate the role of C1q in MI/R; 2) Determine the mechanism of MBL-dependent injury following MI/R.