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

描述（由申请人提供）：已证明牙周炎感染会增加动脉粥样硬化的发病率和严重程度，目前动脉粥样硬化是美国发病率和死亡率的头号原因。此外，越来越多的证据表明肥胖是动脉粥样硬化的主要危险因素，与牙周病有关。在动脉粥样硬化中，最早的病变包含吞噬和积累修饰的脂蛋白的巨噬细胞。持续的单核细胞募集和血管壁中的胆固醇积累促进慢性疾病进展。参与血管修复和稳态的microRNA的几个子集的鉴定使其成为动脉粥样硬化研究的有吸引力的靶点。最近的研究已经将miR-126鉴定为血管完整性和血管生成的重要介质，其通过调节血管内皮生长因子1信号传导和调节血管粘附蛋白来控制白细胞穿过血管壁的运输。在动脉粥样硬化相关的病理学中，显示通过激活CXCL 12/CXCR 4轴以在损伤部位动员和掺入内皮祖细胞来减小血管病变的尺寸。由于来源于骨髓造血干细胞（HSC）的巨噬细胞是动脉粥样硬化的起始和进展的关键，因此在巨噬细胞中过表达有益基因和/或敲低有害基因或使用巨噬细胞作为递送机制的治疗潜力在基因治疗领域获得关注。我们的假设是，巨噬细胞中miR-126的过表达将通过减少动脉粥样硬化斑块形成和增加斑块稳定性来介导动脉粥样硬化保护作用。通过使用我们的合成巨噬细胞促进剂，我们的实验室以前已经能够分别在动脉粥样硬化和神经变性研究中利用巨噬细胞作为肝X受体α和脑源性神经营养因子的递送机制。本研究的目的是确定1）巨噬细胞是否可以成功地将miR-126递送至血管内皮，2）将miR-126递送至血管壁是否保护内皮从而减少动脉粥样硬化病变，以及3）这种保护/减少病变是否由CXCL 12/CXCR 4轴介导。解决这些问题对于推进血管基因治疗在临床上的应用和发现血管再生和重塑的替代方法将是重要的。这项研究计划支持申请人的职业目标所需的培训，成为一名研究再生牙科转化研究的牙科科学家。

DESCRIPTION (provided by applicant): 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.