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

网络医学和系统药理学推进联合肺动脉高压的精准医学

• 批准号: 10625481
• 负责人: Evan L Brittain
• 金额: $ 65.35万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625481
• 关键词: Academic Medical Centers; Activities of Daily Living; Address; Attention; Autopsy; Biochemical Markers; Biological Markers; Biology; Blood Vessels; Blood capillaries; Cardiovascular Diseases; Cessation of life; Clinical; Clinical Trials; Collaborations; Complex; Cross-Over Trials; Data; Development; Diagnosis; Disease; Experimental Models; Fibrosis; Genetic; Heart Diseases; Heart failure; Heterogeneity; Histologic; Human; Hypertrophic Cardiomyopathy; In Situ; Individual; Individual Differences; Left; Lung; Maps; Medicine; Methods; Mission; Molecular; National Heart, Lung, and Blood Institute; Outcome; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Placebo Control; Plasma; Prognosis; Proteins; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary arterial remodeling; Reporting; Research; Safety; Sampling; Severities; System; Testing; Tissues; United Kingdom; United States National Institutes of Health; Validation; Variant; Vascular remodeling; Vulnerable Populations; Work; analytical method; arterial remodeling; biobank; biomarker discovery; candidate marker; clinical heterogeneity; cohort; endophenotype; experimental study; functional status; hemodynamics; high risk; human disease; improved; in silico; individual patient; innovation; mortality; next generation; novel; precision medicine; prognostic; prognostication; protein expression; protein protein interaction; pulmonary arterial hypertension; pulmonary vascular disorder; pulmonary venous hypertension; sex; therapeutic candidate; therapeutic target; transcriptome; treatment response; venule

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.

抽象的 左心衰竭引起的肺动脉高压（pH）是一种常见且高病态的疾病，其特征是 分子，组织表型和临床异质性，会阻碍诊断和治疗靶点的进展 发现。缺乏左心衰竭患者的生化标记和治疗。一些患者 左心疾病发展前后毛细血管pH（CPH），其特征是严重升高 肺血管抗性，血管重塑和早期死亡。这个血管剖面不能归因于 仅到肺静脉高血压（PVH）。例如，我们表明与PVH相比 CPH年轻，但左心脏病的持续时间和严重程度相似。我们还报告了遗传 CPH的特征与PVH患者不同，但在CPH患者中也有很高的分歧。这 观察与CPH尸检时观察到的血管重塑的复杂模式一致，并且 共同表明，可能存在机会来利用单个CPH的独特病理生物学特征 优化诊断和治疗的患者。 我们介绍了引入网络医学的初步数据，以利用独特的病原体特征 患有复杂左心脏病的患者与pH有关。我们开发了特定于患者的网络专注于 在功能/物理蛋白质蛋白质相互作用（PPI）上，为每个生成独特的分子“接线图” 病人。网络拓扑预测肺血液动力学和组织组织学特征（例如纤维化） 个别患者希望整个队列中的表型异质性。因此，我们建议使用它 在CPH中推进精度医学的方法，这为我们的中心假设设定了框架：在CPH中， 跨患者特异性PPI网络的共享功能将识别基于的下一代生物标志物 在功能性分子途径上，疾病特异性和预后。我们还假设针对PPI独特 对于使用系统药理学的个别患者，将为个性化药物治疗提供新颖的途径。 在AIM 1中，我们将介绍CPH，PVH和肺动脉高压（PAH）转录组（n = 50/组）以识别所有CPH患者共享但与PVH/PAH不同的PPI。我们将使用 内型型富集，网络拓扑，遗传环境和蛋白质表达数据作为过滤器，以识别 下一代CPH生物标志物在Silico中的候选者。最后，我们将验证CPH生物标志物的关联 在两个外部人群和人类肺样本中具有功能能力和预后。在AIM 2中，我们将整合 药物蛋白质相互作用和PPI网络数据以识别患者特异性的重新利用疗法并使用功能 遗传学，药物效应蛋白质表达数据以及过滤疗法的药物可用性和安全性 候选人。最后，我们将使用机械终点执行五个安慰剂对照的跨界试验 测试我们系统药理学管道的有效性以进行个性化药物选择。这些创新的 实验可以提高CPH的精度，这是一种缺乏治疗的高病态疾病。