miR-103a-1靶向调控ADAM10在腹主动脉瘤治疗中的实验研究

ADAM10, as a key pro-inflammatory enzyme, appears to be a crucial regulator of infiltration of inflammatory cells. Elevated expression of ADAM has been observed in human abdominal aortic aneurysm (AAA) tissue. Through our bioinformatic analysis and in vitro studies, we identified ADAM10 is a major target of miR-103a-1 in human aortic endothelial cells and human aortic smooth muscle cells. These data suggest that targeting ADAM10 by miR-103a-1 holds therapeutic potential promise for AAA. Interestingly, human AAA and AngII treated ApoE-/- mice displayed miR-103a-1 downregulation, correlating inversely with ADAM10 expression, which further implicate miR-103a-1/ADAM10 in the pathogenesis of AAA..Given the importance of miR-103a-1/ADAM10 in AAA development, we are going to test whether miR-103a-1 is effective to suppress inflammatory reactions in the aortic wall of angiotensin II–infused ApoE−/− mice. We also want to know whether in vivo administration of miR-103a-1 could decrease AAA incidence, mortality, and abdominal aorta dilation in murine models of AngII-infused AAA. Moreover, we are going to explore whether plasma levels of miR-103a-1 and ADAM10 are altered in patients with AAA, and associated with AAA risk and aortic size. Finnally, effect of genetic variant on miR-103a-1/ADAM10 axis will also be investigated. Our project will not only define the utility of altered miR-103a-1/ADAM10 levels in the diagnosis and evaluation of AAAs, but also will provide a new and safer therapeutic tool for the control of AAA.

去整合素与金属蛋白酶10（ADAM10）是调控炎症细胞浸润的关键促炎酶，其表达水平在腹主动脉瘤（AAA, abdominal aortic aneurysm）中显著上升。我们使用生物信息学方法找到了可以调节ADAM10表达的miR-103a-1，而且发现miR-103a-1的表达降低与AngII-ApoE-/-小鼠和人体AAA组织内ADAM10的表达升高有关。下一步，我们准备对AngII-ApoE-/-小鼠注射miR-103a-1，观察调控miR-103a-1/ADAM10 axis对动脉壁炎症，以及对AAA发展，扩张和破裂的影响；同时我们还将在人体内研究miR-103a-1/ADAM10做为AAA生物标志物的可能性，以及遗传变异对miR-103a-1/ADAM10 axis的影响。本项目不仅可以发现新的AAA鉴别诊断、预后预测的分子标志物，也可为AAA的治疗提供全新的分子治疗策略。

ADAM10作为脱落酶（sheddase）可以通过裂解多种细胞表面分子，如细胞因子、粘附分子及生长因子受体胞外域等，而在炎症、癌症等疾病中发挥重要的作用。因此，调控ADAM10的表达或者活性成为多种炎症相关疾病的重要治疗策略。在前期研究结果中，我们在腹主动脉瘤的临床样本中发现了ADAM10 蛋白表达升高的现象，提示ADAM10 可能参与了AAA 的病理过程；之后，我们证实了miR-103a-1 对ADAM10 表达的负调控作用，而且发现血管紧张素Ⅱ（AngII）诱导的ApoE-/-小鼠会出现ADAM10 表达升高以及miR-103a-1 表达降低的负相关现象。这些结果提示Ang II 敏感的miR-103a-1/ADAM10 可能是AAA 的潜在治疗靶点。.以上述研究结果为基础，我们通过促进AAA模型小鼠内miR-103a-1表达，希望通过恢复miR-103a-1对ADAM10的调控达到防治AAA的目的；并且深入研究miR-103a-1和ADAM10的表达水平变化，miR-103a-1对炎症反应、胶原降解的影响及探究血浆miR-103a-1/ADAM10作为AAA biomarker的可能性；