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.
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.
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