Cause and effect of transient changes in stress, gene expression, and RV fiber orientation during RV remodeling, and its impact on RV function and inter-ventricular coupling in pulmonary hypertension

项目摘要 肺动脉高压（PH）是一种心肺疾病， 心室（RV）衰竭。目前还没有针对RV的获批疗法， 研究的重点是减少纤维化，虽然目前还不清楚这是否会最终改善RV 泵送功能然而，胶原蛋白和心肌细胞纤维的取向可能与心肌细胞的生长有关。 对RV功能的主要影响，在正在进行的研究和临床中很大程度上被忽视 实践此外，LV在RV功能中的作用几乎完全被忽略，但 从90年代开始的先前研究已经表明，左心室（LV）对于 RV功能优于RV游离壁收缩。 我们以前的数据表明，左心室收缩的机制是完全不同的， PH儿童和肺动脉结扎（PAB）后的小鼠。此外，委员会认为， 我们实验室中对心脏的数学模拟表明， 重塑和压力超载的RV可能会导致我们在这两种情况下看到的机械问题， 然而，两个关键的问题仍然没有答案： RV结构的变化影响RV和LV收缩力学，以及这些变化如何影响 LV收缩力学影响RV功能？ 在这项研究中，我们将联合收割机结合PAB小鼠模型与计算机模拟， 研究RV游离壁中RV纤维方向和硬化的变化如何影响RV 泵送功能然后，我们将联合收割机PAB与主动脉缩窄术相结合，研究RV如何影响主动脉缩窄术的疗效。 重构干扰LV扭转，如果这中断LV到RV的机械辅助， 心脏收缩期。最后，通过收集成像和基因表达的时间过程数据集，我们 将确定直接受到机械应力变化影响的基因，以及它们如何 触发了下游的重塑途径 通过弥合基因表达、结构、功能和心室间的差距 收缩力学，这个项目可能会导致更好地理解适应与。 适应不良的重塑途径此外，我们的研究重点是确定那些 对功能影响最大的重塑特征， 表达途径，将作为未来研究的药物靶点。

PROJECT SUMMARY Pulmonary hypertension (PH) is a cardiopulmonary disease that ultimately leads to right ventricular (RV) failure. Currently there are no approved therapies targeting the RV and most research is focused on reducing fibrosis, although it is unclear if this will ultimately improve RV pumping function. However, the orientation of collagen and cardiomyocyte fibers likely have a major influence on RV function and are largely overlooked in ongoing research and clinical practice. Furthermore, the role of the LV in RV function is almost completely discounted, but previous research from the 90’s has suggested that the left ventricle (LV) is more important for RV function than the contracting RV free wall. Our previous data has shown that the mechanics of LV contraction is drastically different in children with PH and in mice after pulmonary arterial banding (PAB). Furthermore, mathematical simulations of the heart in our lab have shown that the mechanical burden of the remodeling and pressure-overloaded RV can result in the mechanistic problems we see in both ventricles in children with PH. However, two critical questions remain unanswered: how do changes in RV structure impact RV and LV contractile mechanics, and how do these changes in LV contractile mechanics impact RV function? In this study, we will combine the PAB mouse model with in silico simulations to investigate how changes in RV fiber orientation and stiffening, in the RV free wall, impact RV pumping function. Then, we will combine PAB with aortic constriction to study how RV remodeling interferes with LV torsion and if this interrupts LV-to-RV mechanical assistance during systole. Finally, by collecting a time course dataset of imaging and gene expression, we will identify genes that are directly impacted by changes in mechanical stress and how they trigger their downstream remodeling pathways. By bridging the gap between gene expression, structure, function, and inter-ventricular contractile mechanics, this project could lead to a better understanding of adaptive vs. maladaptive remodeling pathways. Furthermore, our research is focused on identifying those remodeling characteristics with the biggest influence on function and could expose gene expression pathways that will serve as drug targets in future studies.