Multi-scale Investigation of Sex Differences in Right Ventricular Function via Estrogen-Microtubule Interactions

项目摘要 肺动脉高压(PAH)是一种致命性疾病，中位生存期仅为5-7年。 在病理生理学上，PAH是一种进行性毛细血管前血管病变，它增加了 在降低肺动脉顺应性的同时降低肺动脉压和肺血管阻力。 肺血管的变化增加了右心室的工作负荷，最终导致 右室功能不全(RVD)。RVD的存在是PAH死亡的最大危险因素； 然而，目前还没有直接针对RV的PAH疗法。在这项建议中，我们将调查 假设PAH患者右室功能的性别差异部分是由雌激素的抑制作用介导的 关于微管动力学。我们将使用最先进的显微镜和计算分析来定义 雌激素调节微管。然后，在翻译研究中，我们将确定雌激素的调节- 应用高级血流动力学研究临床前PAH患者微管相互作用对右心功能的影响 RV微管细胞骨架的分子表型。

Project Summary Pulmonary arterial hypertension (PAH) is a lethal disease with a median survival of only 5-7 years. Pathophysiologically, PAH is a progressive vasculopathy of the precapillary pulmonary vessels that increases pulmonary arterial pressures and pulmonary vascular resistance while reducing pulmonary arterial compliance. The changes in the pulmonary vasculature augment the work load of the right ventricle, which ultimately results in right ventricular dysfunction (RVD). The presence of RVD is the greatest risk factor for death in PAH; however, no current PAH therapies actually target the RV directly. In this proposal, we will investigate the hypothesis that sex-differences in RV function in PAH are in-part mediated by an inhibitory action of estrogen on microtubule dynamics. We will employ state of the art microscopy and computational analysis to define how estrogen regulates microtubules. Then, in translational studies we will determine modulation of the estrogen- microtubule interaction impacts right ventricular function in pre-clinical PAH using advanced hemodynamics and molecular phenotyping of the RV microtubule cytoskeleton.