Pulmonary Hypertension in Left Heart Disease

左心病肺动脉高压

• 批准号: 10656879
• 负责人: Barry A. Borlaug
• 金额: $ 80.35万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656879
• 关键词: Address; Adult; Aerobic; Anatomy; Animal Model; Autopsy; Back; Bioinformatics; Biological; Biology; Blood Vessels; Blood capillaries; Circulation; Classification; Clinical; Data; Disease; Epidemiology; Exertion; FRAP1 gene; Functional disorder; Glean; Goals; Heart Diseases; Histologic; Human; Knowledge; Left; Life Expectancy; Link; Localized Disease; Location; Lung; Lung diseases; Mass Spectrum Analysis; Mediating; Miniature Swine; Morbidity - disease rate; Nature; Neonatal; Outcome Study; Outcomes Research; Pathway interactions; Patients; Phenotype; Prognosis; Proteins; Proteomics; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary arterial remodeling; Research; Rho-associated kinase; Severities; Signal Transduction; Sirolimus; Structure of parenchyma of lung; Symptoms; System; Techniques; Terminology; Therapeutic; Therapeutic Agents; Vascular remodeling; Venous; Ventricular; Work; differential expression; effective therapy; fasudil; hemodynamics; individualized medicine; innovation; kinase inhibitor; laser capture microdissection; mortality; novel; novel strategies; novel therapeutics; porcine model; pressure; programs; pulmonary arterial hypertension; pulmonary arterial pressure; pulmonary vascular disorder; pulmonary venous hypertension; response; right ventricular failure; stem; symptomatic improvement; therapeutic target; transcriptomics; treatment response; vasoconstriction

PROJECT SUMMARY / ABSTRACT Left heart disease (LHD) leads to pulmonary hypertension (PH-LHD, aka Group 2 PH), right ventricular (RV) failure, and increased mortality and morbidity. Advances in pulmonary vascular biology gleaned from study of the pulmonary arterial (PA) circulation in Group 1 PH and relevant animal models have led to effective therapies for Group 1 PH. Trials of Group 1 PH therapies in PH-LHD have shown highly variable (favorable, neutral or harmful) effects. We propose that two critical knowledge gaps contribute to variability in therapeutic response and impede progress in treating PH-LHD: (1) the lack of a mechanistically informative hemodynamic classification system defining the nature (vasoconstriction vs remodeling) and location (PA vs pulmonary venous (PV)) of pulmonary vascular disease in LHD, and (2) lack of understanding of vessel specific (PV vs PA) biological pathways mediating pulmonary vascular disease in PH-LHD. The objective of this proposal is to address these knowledge gaps and enable therapeutic innovation in PH-LHD. Based on extensive preliminary studies in human and experimental (Exp) PH-LHD, our central hypothesis is that PH-LHD is a phenotypically diverse entity whose ultimate therapeutic approach will be defined by unique hemodynamic phenogroups and vessel specific (PA vs PV) pathophysiological perturbations. In human and Exp PH-LHD, we will use novel hemodynamic assessments to phenotype PH-LHD according to pulmonary vascular resistance (PVR), vasoreactivity, and the longitudinal distribution of PVR (Aim 1). Findings will be validated in human PH-LHD by assessing phenogroup-specific differences in aerobic capacity, RV reserve function and exertional lung congestion. Findings in Exp PH-LHD will be validated by defining PA and PV remodeling (quantitative histomorphometry). Our broad hypothesis is that both the primary mechanism and location of the elevated PVR in PH-LHD have clinical implications and anatomical underpinnings. In human and Exp PH-LHD, we will then (Aim 2) use histochemical, proteomic, and transcriptomic based techniques and bioinformatic analyses to define vessel specific mechanisms across PH-LHD phenogroups. These studies will couple the Aim 1 hemodynamic phenotyping approach to vessel specific vascular biology. In Aim 3, we will determine if therapeutic agents based on our omics studies in human and Exp PH-LHD will ameliorate PV or PA remodeling and delay the progression of PH in Early or Late Exp PH-LHD phenogroups. The research outcome from this work will be a new hemodynamic classification of PH-LHD linked to specific pathophysiology and therapeutic targets, thus enabling individualized medicine approaches to PH-LHD.

项目摘要/摘要 左心疾病(LHD)导致肺动脉高压(PH-LHD，又名第二组PH)、右室(RV) 失败，并增加死亡率和发病率。肺血管生物学研究进展 第一组肺动脉高压的肺动脉循环和相关动物模型已导致有效的治疗 对于第一组PH。1组PH疗法在PH-LHD中的试验显示有很大的变异性(有利、中性或 有害)影响。我们提出两个关键的知识差距导致治疗反应的可变性。 并阻碍了治疗PH-LHD的进展：(1)缺乏机械性信息的血流动力学 定义性质(血管收缩与重塑)和位置(PA与肺静脉)的分类系统 (2)对血管特异性缺乏了解(PV与PA)。 PH-LHD肺血管疾病的生物学途径。这项建议的目的是 解决这些知识差距，实现PH-LHD的治疗创新。基于广泛的初步调查 在人类和实验性(Exp)PH-LHD的研究中，我们的中心假设是PH-LHD是一种表型 不同的实体，其最终治疗方法将由独特的血流动力学表型组和 血管特异性(PA与PV)病理生理紊乱。在人类和Exp PH-LHD中，我们将使用新颖 根据肺血管阻力(PVR)对PH-LHD表型进行血流动力学评估 血管反应性和PVR的纵向分布(目标1)。这些发现将在人类PH-LHD中得到验证 评估不同表型组在有氧能力、右室储备功能和用力肺方面的差异 拥堵。Exp PH-LHD的发现将通过定义PA和PV重塑(量化)来验证 组织形态计量学)。我们广泛的假设是PVR升高的主要机制和位置 在PH-LHD中有临床意义和解剖学基础。在人类和实验PH-LHD中，我们将 (目标2)使用组织化学、蛋白质组学和转录组学技术和生物信息学分析来确定 跨PH-LHD表型组的血管特异性机制。这些研究将结合目标1血流动力学 血管特异性血管生物学的表型方法。在目标3中，我们将确定治疗剂是否基于 我们对人和实验性PH-LHD的组学研究将改善PV或PA重塑并延缓进展 早、晚期实验性PH-LHD表型组的PH值。这项工作的研究成果将是一个新的 PH-LHD的血流动力学分类与特定的病理生理和治疗靶点有关，从而使 PH-LHD的个体化用药途径。