Over-Expression of Microrna-126 in Macrophages for Treatment of Atherosclerosis

Periodontal infection has been shown to increase the incidence and severity of atherosclerosis, which is now the number one cause of morbidity and mortality in the United States. Furthermore there is increasing evidence linking obesity, which is a major risk factor of atherosclerosis, to periodontal disease. In atherosclerosis, the earliest lesions contain macrophages that have phagocytized and accumulated modified lipoproteins. The continued monocyte recruitment and cholesterol accumulation in the vessel wall facilitates chronic disease progression. The identification of several subsets of microRNAs involved in vascular repair and homeostasis have made them an attractive target for atherosclerosis research. Recent studies have identified miR-126 as an essential mediator of vascular integrity and angiogenesis through its regulation of vascular endothelial growth factor 1 signaling, and modulation of vascular adhesion proteins to control leukocyte traffic across the vessel wall. In atherosclerosis related pathology, it was shown to reduce the size of the vascular lesions by activation of the CXCL12/CXCR4 axis to mobilize and incorporate endothelial progenitor cells at the site of injury. Since macrophages derived from bone marrow hematopoietic stem cells (HSC), are key to the initiation and progression of atherosclerosis, the therapeutic potential of over-expressing beneficial genes and/or knocking-down detrimental genes in macrophages, or using the macrophage as a delivery mechanism is gaining attention in the gene therapy field. Our hypothesis is that over-expression of miR-126 in macrophages will mediate atheroprotection by reducing atherosclerosis plaque formation and increasing plaque stability. Through the use of our synthetic macrophage promote, our lab has previously been able utilize the macrophage as a delivery mechanism for Liver X receptor alpha and Brain-derived neurotrophic factor in atherosclerosis and neurodegeneration studies respectively. The goal of this study is to determine 1) if macrophages can successful deliver miR-126 to the vascular endothelium, 2) If delivery of miR-126 to the vessel wall protects the endothelium thereby decreasing atherosclerotic lesions and 3) if this protection/decrease in lesion is mediated by the CXCL12/CXCR4 axis. Answering these questions will be important for advancing the use of vascular gene therapy in a clinical setting and uncovering alternative approaches to vascular regeneration and remodeling. This research proposal supports training necessary for the applicant's career goal to become a dentist-scientist studying translational research in regenerative dentistry. PUBLIC HEALTH RELEVANCE: There is strong association between periodontal disease and cardiovascular disease, thought to be mediated by inflammation and endothelial damage. Furthermore increasing evidence links obesity to the incidence and progression of periodontal disease. The increasing burden of atherosclerosis and the obesity pandemic highlights the demand for improved atherosclerotic therapies involved in vascular repair and regeneration.