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

描述(申请人提供)：牙周感染已被证明会增加动脉粥样硬化的发生率和严重程度，而动脉粥样硬化现在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一个主要风险因素，与牙周病有关。在动脉粥样硬化中，最早的病变包含吞噬并积累修饰脂蛋白的巨噬细胞。持续的单核细胞募集和胆固醇在血管壁的积聚促进了慢性疾病的进展。涉及血管修复和动态平衡的几个microRNAs亚群的鉴定使它们成为动脉粥样硬化研究的一个有吸引力的靶点。最近的研究发现，miR-126通过调节血管内皮生长因子1信号和调节血管黏附蛋白控制白细胞通过血管壁的运输，是血管完整性和血管生成的重要介质。在动脉粥样硬化相关病理学中，研究表明，通过激活CXCL12/CXCR4轴动员和整合损伤部位的内皮祖细胞，可以缩小血管病变的大小。由于骨髓造血干细胞(HSC)来源的巨噬细胞在动脉粥样硬化的发生和发展中起关键作用，因此在巨噬细胞中过度表达有益基因和/或下调有害基因，或利用巨噬细胞作为转运机制的治疗潜力正受到基因治疗领域的关注。我们的假设是，在巨噬细胞中过表达miR-126将通过减少动脉粥样硬化斑块的形成和增加斑块的稳定性来介导动脉粥样硬化保护。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在动脉粥样硬化和神经退行性变的研究中分别利用巨噬细胞作为肝脏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)巨噬细胞是否能成功地将miR-126运送到血管内皮细胞，2)将miR-126运送到血管壁是否保护血管内皮细胞从而减少动脉粥样硬化病变，以及3)这种保护/减少病变是否通过CXCL12/CXCR4轴介导。回答这些问题对于推动血管基因治疗在临床环境中的使用以及发现血管再生和重塑的替代方法将是重要的。这项研究提案支持为申请者的职业目标提供必要的培训，使其成为一名研究再生牙科转化研究的牙医-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.