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

基本信息

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
项目类别：
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

项目摘要

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该候选人目前正在使用综合多组学方法治疗肺动脉高压（PAH）。在大卫格芬医学院肺科和重症监护科发展他的学术生涯他的长期目标是为 PAH 患者开发更有效的靶向疗法。在他的导师 Mansoureh 博士的指导下，对致病机制有了更深入的了解。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，并利用强大的队列整合最新的组学和长期预后。迫切需要计算方法来确定 PAH 肺部潜在的候选分子驱动因素获得最大的人类 PAH 生物库和对照肺部的 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（我们将其称为作为“粉红色”模块），通过与右心的多模式整合与 PAH 肺部密切相关。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，但从未在鉴于越来越多的初步证据表明肺源性粉红色模块的重要性，需要进行更深入的研究。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标。 PAH 中的血管重塑是通过肺血管细胞内的失调来进行的。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 和空间转录组学以及 2) 确定粉红色模块体外敲低的效果拟议的研究将利用 PAH 肺血管细胞中的候选驱动基因，例如 ANTXR1。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 将专注于基础机械和转化研究。