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: 10456651
• 负责人: Edda Frauke Spiekerkoetter
• 金额: $ 41.18万
• 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/10456651
• 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; Hypoxia; Impairment; Ischemia; Knowledge; Lead; Left; Life; Link; Liquid substance; Location; Lung; Medical; Microcirculation; Mission; Modeling; Molecular; 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 Hypertrophy; Right ventricular strain; Right ventricular structure; Risk; Role; Signal Transduction; Snails; Spatial Distribution; Surface; Surgical sutures; Tacrolimus; Testing; Therapeutic; Three-Dimensional Imaging; Tissue constructs; Tissue imaging; Tissues; United States National Institutes of Health; Ventricular; bone morphogenetic protein receptors; cardiac magnetic resonance imaging; 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; right ventricular failure; 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适应性和非适应性重塑的分子和结构机制知之甚少 向房车故障的过渡。当房车不是房车故障的主要原因时，这尤其重要， 但在主要原因得到解决之前，临时支撑房车是可取的。 使肺血管阻力(PVR)正常化和降低RV后负荷的方法将改善RV 功能和反向房车故障。不幸的是，目前还没有可用的药物疗法能够显著地 慢性PAH或血栓栓塞性PH(CTEPH)患者长期减少PVR。由于房车故障是最常见的 PAH中的死亡原因，支持房车以更好地适应增加的后负荷的方法是非常重要的 很受追捧。在本提案中，我们将重点关注使房车面临独特风险的两个病理特征 衰竭：(1)心脏纤维化，降低右室收缩/舒张期功能，破坏心肌结构，以及 损害氧气/营养物质的交换和(2)损害微血管适应(=毛细血管稀疏) 这会导致右室缺血。对于它们在房车适应中的作用，两者都存在争议，也都失败了 就像在康复中。我们使用一种新的小鼠肺动脉结扎(PAB)和去结扎(De-PAB)模型 利用3-D深层组织成像技术定量捕捉右室的组织学变化，并将其与心脏 心脏磁共振成像(CMR)检查。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，我们评估了两种重新用途的药物，他克莫司(FK506) 而我们之前的研究小组表明，enzastaurin可以增加BMPR2信号，通过减少BMPR2信号来帮助RV 心脏纤维化，改善血管适应，加速康复。而且，我们很早就确定了， RV特异性SNAIL1在心脏成纤维细胞中的表达是一种有希望的药物靶点 心脏纤维化。我们推测，用FK506和苯扎托林抑制蜗牛和增加BMPR2将 减轻压力超负荷小鼠心肌纤维化、提高毛细血管密度和改善右室功能 房车。我们的建议有三个重要部分，体现在我们的三个具体目标上：第一，我们将 用基因工具和基因工具靶向控制压力超负荷RV中RV纤维化的分子事件 改用药物以改善PAB小鼠的RV功能和应变，通过CMR评估。第二，我们将 鉴定RV微血管在PAB小鼠和人RV PH组织中的适应性，构建3-RV- 右室微循环的3D模型，以预测右室结构变化如何影响液体和扩散 第三，我们将研究一种新的去带小鼠右室的组织学和功能恢复 模特。通过研究和瞄准房车的适应和失败，我们不仅解决了最重要的 PAH的死亡原因也有助于改善其他疾病，在这些疾病中，轮状病毒是唯一有风险的 慢性肺病、左心疾病、先天性心脏病、慢性心力衰竭等。