Understanding and targeting molecular as well as structural events governing right ventricular adaptation, failure and recovery in pulmonary hypertension using repurposed drugs

使用重新利用的药物了解和靶向控制肺动脉高压右心室适应、衰竭和恢复的分子和结构事件

• 批准号: 10278668
• 负责人: Edda Frauke Spiekerkoetter
• 金额: $ 41.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-25 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10278668
• 关键词: 3-Dimensional; Acute; Address; Architecture; Blood Vessels; Blood capillaries; Cardiac; Cardiac Myocytes; Cause of Death; Cells; Chronic; Clinical; Clinical Trials; Dependence; Diffusion; Disease; Etiology; Event; FK506; Failure; Fibroblasts; Fibrosis; Genetic; Health; Heart Diseases; Histologic; Human Rights; Hypertrophy; Hypoxia; Impairment; Ischemia; Knowledge; Lead; Left; Life; Link; Liquid substance; Location; Lung; Magnetic Resonance Imaging; Medical; Microcirculation; Mission; Modeling; Molecular; Molecular Structure; Molecular Target; Morbidity - disease rate; Mus; Myocardial; Nutrient; Oxygen; Pathologic; Pharmaceutical Preparations; Process; Pulmonary Embolism; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Radial; Recovery; Recovery of Function; Research; Right ventricular structure; Risk; Role; Signal Transduction; Snails; Spatial Distribution; Structure; Surface; Surgical sutures; Tacrolimus; Testing; Therapeutic; Three-Dimensional Imaging; Tissue imaging; Tissues; United States National Institutes of Health; Ventricular; bone morphogenetic protein receptors; congenital heart disorder; coronary fibrosis; density; disability; drug repurposing; druggable target; heart function; histological studies; improved; mortality; mouse model; novel; novel therapeutics; pressure; prevent; pulmonary arterial hypertension; three-dimensional modeling; thrombolysis; tool

Despite the clinical importance of the right ventricle (RV) in pulmonary arterial hypertension (PAH), surprisingly little is known about the molecular and structural mechanisms of RV adaptive and maladaptive remodeling and the transition to RV failure. This is particularly important when the RV is not the primary cause of RV failure, but when a temporary support of the RV would be desirable until the primary cause can be fixed. Approaches that normalize pulmonary vascular resistance (PVR) and reduce RV afterload would improve RV function and reverse RV failure. Unfortunately, no currently available medical therapy is able to significantly reduce PVR long-term in chronic PAH or thromboembolic PH (CTEPH). As RV failure is the most common cause of death in PAH, approaches to support the RV to better adapt to an increased afterload are highly sought after. In this proposal, we will focus on two pathological features that put the RV uniquely at risk for failure: (1) cardiac fibrosis, that reduces RV systolic/diastolic function, disrupts the myocardial architecture, and impairs the exchange of oxygen/nutrients and (2) impaired microvascular adaptation (= capillary rarefaction) that results in RV ischemia. Both are controversially debated as to their role in RV adaptation, failure as well as in recovery. We use a novel mouse model of pulmonary artery banding (PAB) and de-banding (de-PAB) to quantitatively capture histological changes in the RV using 3-D deep tissue imaging and to link them to cardiac function with cardiac MRI (CMR). As a deficiency in Bone morphogenetic protein receptor 2 (BMPR2) signaling is thought to put the RV at risk for failure, we evaluate whether two repurposed drugs, Tacrolimus (FK506) and Enzastaurin, previously shown by our group to increase BMPR2 signaling, assist the RV by reducing cardiac fibrosis and improving vascular adaptation and accelerate recovery. Moreover, we have identified early, RV specific expression of SNAIL1 in cardiac fibroblasts as a promising and druggable target to improved cardiac fibrosis. We hypothesize that Inhibiting Snail and increasing BMPR2 with FK506 and Enzastaurin will reduce cardiac fibrosis, improve capillary density and improve RV function in the pressure overloaded murine RV. Our proposal has three significant parts, which are represented by our three specific aims: First, we will target molecular events that govern RV fibrosis in the pressure overloaded RV with genetic tools and repurposed drugs to improve RV function and strain as assessed by CMR in PAB mice. Second, we will characterize the adaptation of the RV microvasculature in PAB mice and human RV PH tissue, construct a 3- D model of the RV microcirculation to predict how structural changes in the RV influence fluid and diffusion dynamics and third, we will study histological and functional recovery of the RV in a novel de-banding mouse model. By studying and targeting RV adaptation and failure, we not only address the most important cause of mortality in PAH but also help improve other diseases, in which the RV is uniquely at risk for failure such as in chronic lung and left heart disease, CTEPH as well as congenital heart disease.

尽管右心室 (RV) 在肺动脉高压 (PAH) 中具有临床重要性，但令人惊讶的是 关于 RV 适应性和适应不良重塑的分子和结构机制知之甚少 过渡到 RV 故障。当 RV 不是 RV 故障的主要原因时，这一点尤其重要， 但在主要原因得到解决之前需要对 RV 进行临时支持。 使肺血管阻力 (PVR) 正常化并减少 RV 后负荷的方法将改善 RV 功能和反向 RV 故障。不幸的是，目前没有可用的药物治疗能够显着 长期降低慢性 PAH 或血栓栓塞性 PH (CTEPH) 患者的 PVR。由于 RV 故障是最常见的 PAH 的死亡原因，支持 RV 更好地适应增加的后负荷的方法非常重要 被）追捧。在本提案中，我们将重点关注使 RV 面临独特风险的两种病理特征 衰竭：(1) 心脏纤维化，降低右心室收缩/舒张功能，破坏心肌结构，以及 损害氧气/营养物质的交换，并且 (2) 微血管适应受损（=毛细血管稀疏） 导致右心室缺血。两者在 RV 适应和失败中的作用都存在争议 就像在恢复中一样。我们使用一种新型的肺动脉结扎（PAB）和去结扎（de-PAB）小鼠模型来 使用 3D 深部组织成像定量捕获 RV 的组织学变化，并将其与心脏联系起来 心脏 MRI (CMR) 的功能。骨形态发生蛋白受体 2 (BMPR2) 信号传导缺陷 被认为会使 RV 面临失败的风险，我们评估是否有两种重新利用的药物，他克莫司 (FK506) 和 Enzastaurin（我们小组先前已证明可以增加 BMPR2 信号传导）通过减少 心脏纤维化，改善血管适应，加速康复。此外，我们很早就发现， 心脏成纤维细胞中 SNAIL1 的 RV 特异性表达是改善心脏功能的有希望且可药物化的靶点 心脏纤维化。我们假设用 FK506 和 Enzastaurin 抑制 Snail 并增加 BMPR2 减少压力超负荷小鼠的心脏纤维化，提高毛细血管密度并改善右心室功能 房车。我们的提案分为三个重要部分，这三个部分代表了我们的三个具体目标：首先，我们将 利用遗传工具，针对压力超载的 RV 中控制 RV 纤维化的分子事件， 根据 PAB 小鼠 CMR 评估，重新调整药物以改善 RV 功能和应变。其次，我们将 表征 PAB 小鼠和人类 RV PH 组织中 RV 微脉管系统的适应，构建 3- 右心室微循环 D 模型，用于预测右心室结构变化如何影响液体和扩散 第三，我们将研究新型解带小鼠 RV 的组织学和功能恢复 模型。通过研究和针对 RV 适应和故障，我们不仅解决了最重要的问题 RV 不仅是 PAH 死亡的原因，而且还有助于改善其他疾病，其中 RV 面临着独特的风险 慢性肺病和左心病、CTEPH 以及先天性心脏病等衰竭。