Role for Nrf2 and exercise in mitigating pulmonary hypertension-induced vascular dysfunction

Nrf2 和运动在减轻肺动脉高压引起的血管功能障碍中的作用

基本信息

批准号：
10750500
负责人：
Kiana Marie Schulze
金额：
$ 3.56万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750500
关键词：
Acetylcholine Anatomy Animal Disease Models Antioxidants Blood Vessels Blood flow Cardiac Cessation of life Coronary Critical Thinking Data Dependence Development Disease Educational process of instructing Elements Endothelium Environment Exercise Foundations Functional disorder Gases Goals Health Heart Heart failure Impairment Incubated Inflammatory Kansas Kinesiology Knock-out Knowledge Laboratories Measurement Measures Medial Mediator Messenger RNA Microspheres Mitochondria Molecular Muscle Fatigue Muscle Weakness Muscle function Myocardium Outcome Oxidation-Reduction Oxidative Stress Oxygen Pathogenesis Pathway interactions Patients Perfusion Physiological Physiology Preparation Pulmonary Hypertension Quality of life Rattus Reactive Oxygen Species Regimen Regulation Relaxation Research Resistance Respiration Respiratory Diaphragm Respiratory Muscles Respiratory physiology Role Skeletal Muscle Structure Sulforaphane Techniques Testing Time Training Transcriptional Activation Treatment Efficacy Universities Up-Regulation Vascular Diseases Vascular resistance Vasodilation Vasomotor Work Workload arteriole base career cytokine design endothelial dysfunction exercise intervention exercise intolerance exercise training experimental study frontier heart function improved in vivo insight meter novel nuclear factor-erythroid 2 oxidative damage pharmacologic preservation protein expression pulmonary vascular remodeling right ventricular failure sedentary skills therapeutic development therapeutic target transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (PH) is a disease characterized by pulmonary vascular remodeling and poor gas exchange, and eventually leads to right ventricular failure and death. Elevated heart and respiratory muscle workloads contribute to diaphragm and cardiac impairments in PH; however, the physiological and molecular bases are not fully understood. Vascular function is compromised in PH, resulting in an inability to match oxygen delivery to demand, which is of increasing importance in the overworked diaphragm and heart. However, the mechanisms underlying PH-induced vascular dysfunction and, arguably more important, targets for mitigating such dysfunction remain unknown. Upregulation of reactive oxygen species and inflammatory cytokines are thought to promote PH pathogenesis, which suggests that modulation of intracellular redox pathways may serve as one potential mechanism responsible for the impaired vasomotor control with PH and provides a potential therapeutic target to improve the compromised vascular function in PH. Preliminary data supports that PH impairs endothelial-dependent and -independent vasorelaxation in diaphragm arterioles, and therefore diaphragmatic blood flow. Importantly, endothelial-dependent and - independent vasoreactivity may be improved by activation of the transcription factor, nuclear factor erythroid- 2–related factor 2 (Nrf2). However, the role of Nrf2 in improving coronary and diaphragm vascular function in PH has never been determined. Therefore, our global hypothesis is that exercise training and pharmacological Nrf2 activation will improve or restore coronary and diaphragm vascular function in PH. Furthermore, we will assess the reliance upon Nrf2 for these adaptations in order to determine the potential molecular basis for our findings. This project will be completed at Kansas State University (KSU) under the guidance of Drs. David C. Poole and Bradley J. Behnke. The training plan has been formulated to facilitate the development of technical proficiencies and critical thinking skills needed to execute the proposed experiments and incorporates the elements essential for the applicant to transition into an independent scientific career. The Poole and Behnke Laboratories, and the Departments of Kinesiology and Anatomy and Physiology at KSU represent a rich scientific environment that will provide outstanding graduate training and research opportunities to gain new insights into mechanisms of diaphragm blood flow regulation and vasomotor control in healthy and diseased animal models.

项目概要/摘要肺动脉高压（PH）是一种以肺血管重塑和气体流通不良为特征的疾病交换，最终导致右心室衰竭和死亡。然而，工作负荷会导致肺动脉高压患者的膈肌和心脏损伤；碱基尚未完全了解 PH 中的血管功能会受到损害，导致无法匹配。按需输送氧气，这对于过度劳累的隔膜和心脏来说越来越重要。然而，PH 引起的血管功能障碍的机制，可以说更重要的是，目标缓解这种功能障碍的作用仍然未知。细胞因子被认为促进 PH 发病机制，这表明细胞内氧化还原的调节通路可能是导致 PH 和 PH 导致的血管舒缩控制受损的一种潜在机制。为改善 PH 中受损的血管功能提供了潜在的治疗靶点。初步数据支持 PH 损害内皮依赖性和非依赖性血管舒张作用膈肌小动脉，因此膈肌血流量重要的是，内皮依赖性和 - 独立血管反应性可以通过激活转录因子、核因子红细胞- 2-相关因子 2 (Nrf2) 然而，Nrf2 在改善冠状动脉和膈血管功能中的作用。因此，我们的总体假设是运动训练和 PH 从未确定。药理学 Nrf2 激活将改善或恢复冠状动脉和膈肌血管功能此外，我们将评估这些适应对 Nrf2 的依赖，以确定我们的发现的潜在分子基础。该项目将在 David C. Poole 博士的指导下在堪萨斯州立大学 (KSU) 完成。和 Bradley J. Behnke 制定了培训计划，以促进技术发展。执行所提议的实验所需的熟练程度和批判性思维技能，并将申请人过渡到独立科学职业所必需的要素普尔和本克。肯塔基州立大学的实验室以及运动机能学、解剖学和生理学系代表了丰富的科学环境将为研究生提供出色的培训和研究机会，以获得新的知识深入了解健康和患病患者膈肌血流调节和血管舒缩控制的机制动物模型。