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：
10614649
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/10614649
关键词：
Antiinflammatory Effect Area Binding Biological Assay Biomedical Engineering Biophysics Blood capillaries 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.

项目概要肺动脉高压（PAH）是一种致命性疾病，中位生存期仅为 5-7 年。从病理生理学角度来看，PAH 是毛细血管前肺血管的进行性血管病变，其增加肺动脉压力和肺血管阻力，同时降低肺动脉顺应性。肺血管系统的变化增加了右心室的工作负荷，最终导致右心室功能障碍（RVD）。 RVD 的存在是 PAH 死亡的最大危险因素；然而，目前的 PAH 疗法实际上没有直接针对 RV。在本提案中，我们将调查假设 PAH 中 RV 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。我们将采用最先进的显微镜和计算分析来定义如何雌激素调节微管。然后，在转化研究中，我们将确定雌激素的调节- 使用先进的血流动力学微管相互作用影响临床前 PAH 的右心室功能和 RV 微管细胞骨架的分子表型。