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

通过雌激素-微管相互作用对右心室功能性别差异进行多尺度研究

基本信息

批准号：
10439249
负责人：
Kurt W Prins
金额：
$ 60.87万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439249
关键词：
Antiinflammatory Effect Area Binding Biological Assay Biomedical Engineering Biophysics Calcium Cardiac Myocytes Cells Cessation of life Computer Analysis Computer Models Cytoskeleton Data Disease Down-Regulation Echocardiography Electron Microscopy Endothelin Estrogen Receptor alpha Estrogens Exhibits Exposure to Female Fibrosis Fluorescence Microscopy Grant Growth Hypoxia Impairment In Vitro Investigation Knowledge Lung Maintenance Mediating Microscopy Microtubule Polymerization Microtubules Mitochondria Molecular Monocrotaline Pathologic Pathway interactions Phenotype Proteins Pulmonary Vascular Resistance Pulmonary artery structure Pulmonary vessels Rattus Regulation Right Ventricular Dysfunction Right Ventricular Function Right ventricular structure Risk Factors Rodent Role Severities Sex Differences Signal Transduction Stimulus Stress Structure Techniques Testing Vascular Diseases Ventricular Women&apos s Rights Workload density experimental study female sex hormone hemodynamics improved in vivo junctophilin male molecular phenotype mortality pre-clinical pressure pulmonary arterial hypertension pulmonary arterial pressure response right ventricular failure trafficking translational approach translational study

项目摘要

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.

项目摘要肺动脉高压（PAH）是一种致命疾病，中位存活仅为5 - 7年。从病理生理上讲，PAH是毛细血管前肺部血管的进行性血管病肺动脉压力和肺血管耐药性，同时降低肺动脉依从性。肺脉管系统的变化增加了右心室的工作负荷，最终导致在右心室功能障碍（RVD）中。 RVD的存在是PAH死亡的最大危险因素。但是，没有当前的PAH疗法实际上直接针对RV。在此提案中，我们将调查假设PAH中RV功能的性别差异是由雌激素的抑制作用介导的在微管动力学上。我们将采用艺术显微镜和计算分析的状态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微管相互作用使用晚期血流动力学影响临床前PAH的右心室功能 RV微管细胞骨架的分子表型。