Network Medicine and Systems Pharmacology to Advance Precision Medicine in Combined Pulmonary Hypertension

摘要 左心衰所致肺动脉高压是一种常见的高致病性疾病，其特征是： 分子、组织表型和临床异质性阻碍了诊断和治疗靶点的进展 的发现缺乏对左心衰竭-PH患者的生化标志物和治疗。部分患者 左心疾病发展为合并毛细血管前和后PH（CPH），其特征为严重升高 肺血管阻力、血管重塑和早期死亡。这种血管轮廓不能归因于 肺静脉高压（PVH）。例如，我们表明，与PVH相比， CPH更年轻，但与左心疾病的持续时间和严重程度相似。我们还报告说， CPH的特征与PVH患者不同，但在CPH患者中也高度不同。这 观察结果与CPH尸检中观察到的血管重塑的复杂模式一致，并且， 总的来说，这表明可能存在利用个体CPH独特病理生物学特征的机会 优化诊断和治疗。 我们提出了初步的数据创新网络医学，以利用独特的病理生物学特征， 与PH相关的复杂左心疾病患者。我们开发了患者特异性网络， 功能/物理蛋白质-蛋白质相互作用（PPI），为每个PPI生成独特的分子“布线图” 病人网络拓扑预测肺血流动力学和组织组织学特征（如纤维化）， 个体患者，尽管整个队列的表型异质性。因此，我们建议利用这个 在CPH中推进精准医疗的方法，为我们的中心假设设定了框架：在CPH中， 跨患者特定PPI网络的共享功能将识别基于的下一代生物标志物 功能性分子通路、疾病特异性和预后。我们还假设，针对PPI的独特性 将系统药理学应用于个体患者，将为个体化药物治疗提供新的途径。 在目标1中，我们将分析CPH、PVH和肺动脉高压（PAH）转录组（N= 10）。 50/组），以确定所有CPH患者共有但与PVH/PAH不同的PPI。我们将使用 内表型富集、网络拓扑、遗传背景和蛋白质表达数据作为筛选器， 下一代CPH生物标志物候选物。最后，我们将验证CPH生物标志物的相关性， 在两个外部队列和人肺样本中研究功能能力和预后。在目标2中，我们将整合 药物-蛋白质相互作用和PPI网络数据，以确定患者特异性的再用途疗法，并使用功能性 遗传学、药物效应-蛋白表达数据以及药物可用性和安全性特征，以筛选治疗药物 候选人最后，我们将使用机械终点进行5项N-of-1安慰剂对照交叉试验 以测试我们的系统药理学管道的有效性，用于个体化药物选择。这些创新 实验推进了CPH的精确医学，CPH是一种缺乏治疗的高度病态疾病。

ABSTRACT Pulmonary hypertension (PH) due to left heart failure is a common and highly morbid disease characterized by molecular, histophenotypic, and clinical heterogeneity that hampers progress in diagnosis and therapeutic target discovery. Biochemical markers and treatments for left heart failure-PH patients are lacking. Some patients with left heart disease develop combined pre- and post-capillary PH (CPH), characterized by severely elevated pulmonary vascular resistance, vascular remodeling, and early death. This vascular profile cannot be ascribed to pulmonary venous hypertension (PVH) alone. For example, we show that compared to PVH, patients with CPH are younger but have a similar duration and severity of left heart disease. We also reported that the genetic profile of CPH is divergent from patients with PVH but is also highly diverse among CPH patients. This observation is consistent with the complex patterns of vascular remodeling observed at autopsy in CPH, and, collectively, suggest that opportunity may exist to leverage the unique pathobiological profile of individual CPH patients for optimizing diagnosis and treatment. We present preliminary data innovating network medicine to exploit unique pathobiological features in patients with a complex left heart disease associated with PH. We developed patient-specific networks focusing on functional/physical protein-protein interactions (PPIs), generating a unique molecular ‘wiring map’ for each patient. Network topology predicted pulmonary hemodynamics and tissue histologic features (e.g. fibrosis) in individual patients despite phenotypic heterogeneity across the cohort. Therefore, we propose to use this approach to advance precision medicine in CPH, which sets the framework for our central hypothesis: In CPH, shared features across patient-specific PPI networks will identify next-generation biomarker(s) that are based on functional molecular pathways, disease-specific, and prognostic. We postulate also that targeting PPIs unique to individual patients using systems pharmacology will provide a novel avenue to individualize drug therapy. In Aim 1 we will profile the CPH, PVH, and pulmonary arterial hypertension (PAH) transcriptome (N= 50/group) to identify PPIs that are shared by all CPH patients, but distinct from PVH/PAH. We will use endophenotype enrichment, network topology, genetic context, and protein expression data as filters to identify next-generation CPH biomarker candidates in silico. Finally, we will validate the CPH biomarkers for associations with functional capacity and prognosis in two external cohorts and human lung samples. In Aim 2 we will integrate drug-protein interaction and PPI network data to identify patient-specific repurposed therapies and use functional genetics, drug effect-protein expression data, and drug availability and safety profiles to filter therapeutic candidates. Finally, we will perform five N-of-1 placebo-controlled cross-over trials using mechanistic endpoints to test the validity of our systems pharmacology pipeline for individualized drug selection. These innovative experiments advance precision medicine in CPH, a highly morbid disease that lacks treatment.