Whole Genome Expression in Mice Containing a Human Mannose Binding Gene (hMBL): Examining the Immunological Role of Monoclonal Antibody (mAb) 3F8 In Attenuating Myocardial Ischemia-Reperfusion Injuries

• Main Author: Gorsuch, William Brian
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2014
• Subjects: Genetics; Molecular biology
• ISBN: 1321463987; 9781321463989

During a myocardial ischemic event, acute occlusion sets in motion cell necrosis and myocardial tissue injury referred to as a myocardial ischemia-reperfusion (MI/R) injury. The resultant injury is triggered by an immunological response of which a major contributor involves the complement cascade of innate immune system involving mannose binding lectin (MBL). Few anti-complement therapeutics however have been approved for clinical use. Those studies to date have involved extensive whole genome expression in murine models of MI/R injury to assist in drug target elucidation. Studies performed have examined genomic traits and expression of mouse MBL (mMBL), which is not one hundred percent homologous to human mannose binding lectin (hMBL). In this study, novel hMBL+/+ mice treated with a novel mAb 3F8 were protected from MI/R injury as measured by area at risk and myocardial infarct staining when compared to control mice. Whole genome expression with the use of microarray was performed between hMBL mice undergoing MI/R treated with either a novel recombinant mAb 3F8 or mAb 1C10 as control. Mice treated with mAb 3F8 compared to mice treated with 1C10 revealed a significant down regulation in uncharacterized genes of the lncRNA family. Molecular modeling was used to study the three dimensional structural characteristics of mAb 3F8 recognition of hMBL. Within the hinge region of hMBL three possible locations were identified for the mAb 3F8 epitope for hMBL. These structurally similar locations offer possible insight into the ability of mAb 3F8 in protecting against MI/R injuries. These findings will assist in better understanding the genomic role hMBL in MI/R, the ability of a novel murine mAb 3F8 to modulate those effects and aide in continued drug target elucidation.