Role of miR96 in Pulmonary Arterial Hypertension

肺动脉高压(PAH)是一种存活率很低的破坏性疾病。它更多地发生在妇女身上，涉及到由于肺动脉壁增厚(重塑)而关闭的肺动脉。这会给心脏带来压力，导致右心室衰竭和死亡。5-羟色胺是一种可以引起这种重塑的化学物质，它通过一种名为5HT1b受体的蛋白质起作用。被称为microRNAs的小片段RNA可以调节基因，而microRNA96可以减少5HT1b受体的数量，从而减少5-羟色胺的致病作用。在女性PAH患者或动物模型的肺细胞中，这种microRNA96可能存在缺陷，导致5HT1b受体数量增加。我们已经证明，通过注射的方式使用microRNA96“模拟”恢复肺动脉中microRNA96的水平可以减少5HT1b受体的数量，并可以逆转这种疾病的小鼠和大鼠模型的肺动脉高压。在这里，我们希望充分了解这种模仿是如何工作的。我们还将确定给药的最佳方式，最佳剂量，是否有副作用，以及是否与其他药物一起使用效果更好。

Pulmonary arterial hypertension (PAH) is a devasting disease with a very poor survival rate. It occurs more frequently in women and involves the closing down of lung arteries due to thickening of their walls (remodelling). This puts a strain on the heart and causes failure of the right ventricle of the heart and death. Serotonin is a chemical that can cause this remodelling and it acts via a protein called a 5HT1B receptor. Small pieces of RNA called microRNAs can regulate genes and microRNA96 can decrease the number of 5HT1B receptors thus reducing the disease-causing effects of serotonin. In lung cells from female PAH patients or animal models, there can be a deficiency in this microRNA96 which causes an increase in the number of 5HT1B receptors. We have shown that restoring the levels of microRNA96 in lung arteries using a microRNA96 'mimic' by injection can decrease the number of 5HT1B receptors and can reverse pulmonary hypertension in mouse and rat models of the disease. Here we wish to understand fully how this mimic works. We will also determine the best way to administer the mimic, the best dose, if it has side effects and if it would work better with other drugs.