Integrative Multiomics to Uncover Novel Genes and Networks in Pulmonary Arterial Hypertension

综合多组学揭示肺动脉高压的新基因和网络

• 批准号: 10723950
• 负责人: Jason Hong
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723950
• 关键词: Biology; Blood Vessels; Candidate Disease Gene; Cardiac Catheterization Procedures; Cells; Computer Analysis; Computing Methodologies; Critical Care; Data; Disease; Endothelium; Foundations; Future; Genes; Genetic Risk; Genetic Transcription; Glycoproteins; Goals; Health; Histologic; Human; In Situ; In Vitro; Integrins; Investigation; Knowledge; Lung; Malignant Neoplasms; Measures; Mentors; Mesenchymal; Molecular; Molecular Profiling; Pathogenesis; Pathogenicity; Pathway Analysis; Pathway interactions; Patients; Phenotype; Process; Prognosis; Pulmonary arterial remodeling; Quality of life; Research; Resolution; Role; Sampling; Severities; Small Interfering RNA; System; Testing; Vascular remodeling; WNT Signaling Pathway; biobank; candidate identification; career; cell type; cohort; effective therapy; genome wide association study; hemodynamics; insight; knock-down; medical schools; multimodality; multiple omics; new therapeutic target; novel; physician-scientist training program; pulmonary arterial hypertension; pulmonary vascular cells; pulmonary vascular remodeling; single nucleus RNA-sequencing; skills; targeted treatment; therapeutic target; transcriptome sequencing; transcriptomics; translational study

Project Summary/Abstract This proposal describes a mentored physician-scientist training program to uncover novel genes and networks in pulmonary arterial hypertension (PAH) using an integrative multiomics approach. The candidate is currently developing his academic career in the Division of Pulmonary & Critical Care at the David Geffen School of Medicine of UCLA. His long-term goal is to develop more effective targeted therapies for PAH patients informed by a deeper knowledge of the pathogenic mechanisms. Under the guidance of his mentors Drs. Mansoureh Eghbali and Xia Yang, the candidate will develop a unique cross-disciplinary skillset in integrative systems, single-cell, spatial and experimental biology that will facilitate his transition to research independence in the field of PAH. PAH remains an incurable disease characterized by irreversible pulmonary vascular remodeling, poor quality of life, and guarded long-term prognosis. Leveraging a well-powered cohort integrating the latest omics and computational methodologies is critically needed to identify candidate molecular drivers in PAH lungs as potential therapeutic targets. With access to RNA sequencing of the largest biobank of human PAH and control lungs to date (n=148), we have identified, by co-expression network analysis, a module of 266 genes (which we refer to as the “pink” module) that is strongly associated with PAH lungs. Through multimodal integration with right heart catheterization data, histological analyses, and genome-wide association studies (GWAS), we found the pink module is not only transcriptionally upregulated in PAH lungs, but also associated with increased hemodynamic severity, vascular remodeling, and genetic risk of PAH. Our preliminary data suggests pink module genes are 1) dysregulated in pulmonary vascular cells, 2) enriched in pathways relevant to pulmonary vascular remodeling such as endothelial-mesenchymal transition and Wnt signaling, 3) and may be candidate molecular drivers of PAH, such as ANTXR1, an integrin-like glycoprotein strongly implicated in various cancers but never studied in PAH. Given the mounting preliminary evidence for the importance of the bulk lung-derived pink module, a deeper investigation into its cell-specific role in PAH pathogenesis is needed to advance our understanding of the molecular drivers of PAH lungs and identify new therapeutic targets. We hypothesize that the pink module drives vascular remodeling in PAH through its dysregulation within pulmonary vascular cells. To test this hypothesis, we will 1) resolve the specific cellular context in which the pink module is dysregulated in PAH lungs using single- nucleus RNAseq and spatial transcriptomics and 2) determine the effects of in vitro knockdown of a pink module candidate driver gene, such as ANTXR1, in PAH pulmonary vascular cells. The proposed studies will utilize a combination of cutting-edge multiomic approaches and experimental biology to provide greater insight into a novel PAH-associated gene set derived from a large lung biobank, and will provide a foundation for my own lab and future R01 that will focus on basic mechanistic and translational studies.

项目概要/摘要 该提案描述了一个受指导的医师科学家培训计划，以发现新的基因和网络 使用综合多组学方法治疗肺动脉高压（PAH）。该候选人目前是 在大卫格芬医学院肺科和重症监护科发展他的学术生涯 加州大学洛杉矶分校医学。他的长期目标是为 PAH 患者开发更有效的靶向疗法 通过对致病机制有更深入的了解。在导师博士的指导下。曼苏雷 候选人 Eghbali 和 Xia Yang 将在综合系统中培养独特的跨学科技能， 单细胞、空间和实验生物学将有助于他过渡到该领域的独立研究 多环芳烃。 PAH 仍然是一种无法治愈的疾病，其特征是不可逆的肺血管重塑、肺质量差 生命，并警惕长期预后。利用强大的队列整合最新的组学和 迫切需要计算方法来确定 PAH 肺中潜在的候选分子驱动因素 治疗目标。可以访问最大的人类 PAH 生物库和对照肺的 RNA 测序， 日期（n=148），我们通过共表达网络分析确定了一个包含 266 个基因的模块（我们将其称为 与 PAH 肺部密切相关的“粉红色”模块）。通过多式联运整合右心 通过导管插入数据、组织学分析和全基因组关联研究 (GWAS)，我们发现粉红色 该模块不仅在 PAH 肺中转录上调，而且与血流动力学增加相关 PAH 的严重程度、血管重塑和遗传风险。我们的初步数据表明粉红色模块基因是 1) 肺血管细胞失调，2) 富含与肺血管重塑相关的通路 例如内皮-间质转化和 Wnt 信号传导，3) 并且可能是候选分子驱动因素 PAH，例如 ANTXR1，一种与多种癌症密切相关的整合素样糖蛋白，但从未在 多环芳烃。鉴于越来越多的初步证据表明来自肺的粉红色模块的重要性，更深入的研究 需要研究其在 PAH 发病机制中的细胞特异性作用，以增进我们对 PAH 发病机制的理解。 PAH 肺部的分子驱动因素并确定新的治疗靶点。我们假设粉色模块驱动 PAH 中的血管重塑是通过肺血管细胞内的失调来实现的。为了检验这个假设， 我们将1）解决PAH肺中粉红色模块失调的特定细胞环境，使用单 核 RNAseq 和空间转录组学，2) 确定粉红色模块体外敲低的效果 PAH肺血管细胞中的候选驱动基因，例如ANTXR1。拟议的研究将利用 尖端多组学方法和实验生物学的结合，可以更深入地了解 来自大型肺部生物库的新型 PAH 相关基因组，将为我自己的实验室提供基础 未来的 R01 将侧重于基础机制和转化研究。