Collagen Accumulation & Mechanical Mechanisms in Pulmonary Hypertension

胶原蛋白堆积

基本信息

批准号：
8912626
负责人：
Naomi C Chesler
金额：
$ 10万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8912626
关键词：
Arteries Blood Vessels Caliber Cause of Death Charge Chronic Clinical Collaborations Collagen Communities Coupled Dependence Development Disease Disease Progression Distal Drops Exercise Experimental Designs Failure Fibrosis Funding Future Goals Gray unit of radiation dose Health Heart Heart failure Hypertension Hypertrophy Hypoxia Knowledge Lead Light Link Lung Lung Compliance Measures Mechanics Methods Modeling Mus Myocardium Physiologic pulse Proteins Pulmonary Circulation Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Pulse Pressure Research Resistance Right Ventricular Dysfunction Right Ventricular Function Right Ventricular Hypertrophy Role Severities Solid Testing Thick Tissues Training Transgenic Mice Ventricular Ventricular Remodeling Work arterial remodeling crosslink design electric impedance hemodynamics improved mortality novel pressure pulmonary arterial hypertension

项目摘要

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a progressive and rapidly fatal disease, even with modern therapies. The cause of death is typically right ventricular (RV) failure. Narrowing of the small, distal pulmonary arteries is know to cause PAH. Recently, increased stiffness of the large, proximal pulmonary arteries (PAs) was identified as a powerful predictor of mortality in PAH. However, the impact of distal and proximal PA remodeling on the critical transition from a healthy RV to a failing RV remains a major knowledge gap. Over the initial funding period (2008-2012), we focused on the vascular impact of the mechanically important protein collagen on proximal arterial stiffening, pulmonary hemodynamics and subsequent changes in RV function with hypoxia-induced pulmonary hypertension (HPH). Here we extend the work in three important ways. First, we employ novel methods to generate not only RV dysfunction but also RV failure, which has been a limitation of mouse PH models until recently. Second, we designed a novel experimental approach to uncouple and therefore distinguish the effects of proximal PA stiffening from distal PA narrowing, which are tightly coupled clinically but may impair RV function through independent mechanisms. Third, we investigate the role of RV collagen content and cross-linking in RV dysfunction and the transition to failure. Our aims are: Aim 1. To demonstrate the dependence of adaptive RV hypertrophy (thickened but not failing RV) on distal PA narrowing and independence from proximal PA stiffening in mild/moderate PAH, because we hypothesize that increases in mean pulmonary arterial pressure due to distal PA narrowing are necessary and sufficient to cause adaptive RV hypertrophy in mild to moderate PAH. Aim 2. To demonstrate the dependence of maladaptive RV remodeling (failing RV) on the combination of distal PA narrowing and proximal PA stiffening in severe PAH, because we hypothesize that increases in mean pulmonary arterial pressure are necessary but not sufficient to cause maladaptive RV remodeling in severe PAH; we hypothesize that increases in pulse pressure induced by proximal PA stiffening are also necessary. Aim 3. To investigate the relationship between RV function and RV fibrosis because we hypothesize that a more fibrotic RV is more impaired by distal PA narrowing and proximal PA stiffening than a less fibrotic RV. The clinical and scientific communities investigating PAH were recently charged with improving our understanding of the dependence of RV function on pulmonary vascular changes. Our goals are to investigate critical mechanobiological changes in proximal and distal PAs as well as the RV itself that drive the transition from a hypertrophied, functional RV to a failing RV during PAH progression, with a particular emphasis on the role of collagen, which in the future may impact treatment options for this rapidly fatal disease.

描述（由申请人提供）：即使采用现代疗法，肺动脉高压（PAH）也是一种进行性且迅速致命的疾病。死亡原因通常是右心室（RV）衰竭。已知远端小肺动脉变窄会导致肺动脉高压。最近，近端大肺动脉 (PA) 僵硬度的增加被认为是 PAH 死亡率的有力预测因素。然而，远端和近端 PA 重塑对从健康 RV 到故障 RV 的关键转变的影响仍然是一个主要的知识空白。在最初的资助期间（2008-2012），我们重点研究了机械上重要的胶原蛋白对近端动脉硬化、肺血流动力学以及缺氧引起的肺动脉高压（HPH）引起的右心室功能的后续变化的血管影响。在这里，我们通过三个重要的方式扩展工作。首先，我们采用新方法不仅产生 RV 功能障碍，而且产生 RV 衰竭，直到最近，这一直是小鼠 PH 模型的局限性。其次，我们设计了一种新颖的实验方法来解耦，从而区分近端 PA 硬化和远端 PA 狭窄的影响，这两种效应在临床上紧密耦合，但可能通过独立机制损害 RV 功能。第三，我们研究了 RV 胶原含量和交联在 RV 功能障碍和向衰竭过渡中的作用。我们的目标是：目标 1. 证明轻度/中度 PAH 中适应性 RV 肥大（RV 增厚但未衰竭）对远端 PA 狭窄的依赖性以及与近端 PA 僵硬的独立性，因为我们假设平均肺动脉压的增加是由于在轻度至中度 PAH 中，远端 PA 狭窄对于引起适应性 RV 肥大是必要且充分的。目标 2. 证明严重 PAH 中适应不良的 RV 重塑（失败的 RV）对远端 PA 狭窄和近端 PA 僵硬的组合的依赖性，因为我们假设平均肺动脉压的增加是必要的，但不足以引起适应不良的 RV 重塑严重肺动脉高压；我们假设近端 PA 硬化引起的脉压增加也是必要的。目标 3. 研究 RV 功能和 RV 纤维化之间的关系，因为我们假设纤维化程度较高的 RV 比纤维化程度较低的 RV 更容易受到远端 PA 狭窄和近端 PA 硬化的损害。临床和科学调查 PAH 的社区最近负责提高我们对 RV 功能对肺血管变化依赖性的理解。我们的目标是研究近端和远端 PA 以及 RV 本身的关键机械生物学变化，这些变化在 PAH 进展过程中驱动从肥大、功能性 RV 向衰竭 RV 的转变，特别强调胶原蛋白的作用，胶原蛋白在未来可能会影响这种迅速致命疾病的治疗选择。