Collagen Accumulation & Mechanical Mechanisms in Pulmonary Hypertension

胶原蛋白堆积

• 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
• 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

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（RV）衰竭。较小的远端肺动脉变窄会导致PAH。最近，较大的近端肺动脉（PA）的刚度增加为PAH死亡率的有力预测指标。但是，远端和近端PA重塑对从健康RV到失败的RV的关键过渡的影响仍然是一个主要的知识差距。在最初的资金期（2008-2012）中，我们着重于机械重要的蛋白质胶原蛋白对近端动脉僵硬，肺部血液动力学和随后的RV功能变化的血管影响，其肺部诱导的肺动脉高压（HPH）。在这里，我们以三种重要方式扩展工作。首先，我们采用新颖的方法不仅会产生RV功能障碍，而且还会产生RV失败，直到最近，这一直是小鼠pH模型的限制。其次，我们设计了一种新型的实验方法来脱离偶发，因此区分了近端PA僵硬与远端PA缩小的影响，远端PA缩小，远端PA缩小，临床上紧密耦合，但可能会通过独立的机制损害RV功能。第三，我们研究了RV胶原蛋白含量和交联在RV功能障碍以及失败的过渡中的作用。我们的目的是：目标1。证明自适应RV肥大（增厚但不会失败的RV）对远端PA的狭窄和独立于轻度/中度PAH的近端PA僵硬，因为我们假设由于远端PA的平均肺动脉压力增加而导致远端较狭窄的远端肺动脉压力是必要的，因此足以使适应性RV适应性适应性RV适应性。目的2。要证明不良适应性RV重塑（RV失败）对严重PAH的远端PA缩小和近端PA僵硬的组合，因为我们假设在严重的PAH中，平均肺动脉压的平均肺动脉压增加是必需的，但不足以引起不足的RV;我们假设还需要近端PA僵硬引起的脉压增加。目的3。研究RV功能与RV纤维化之间的关系，因为我们假设比纤维化的RV远端PA变窄和近端PA僵硬更受纤维化的RV损害。临床和科学 最近，研究PAH的社区被指控提高我们对RV功能对肺血管变化的依赖性的理解。我们的目标是研究近端和远端PAS的关键机械生物学变化以及RV本身，这些变化可以推动从PAH进展过程中从肥厚的，功能性的RV到失败的RV过渡，并特别强调胶原蛋白的作用，这可能会影响这种快速致命疾病的治疗方案。