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.

项目总结/摘要 该提案描述了一个指导医生科学家培训计划，以发现新的基因和网络 在肺动脉高压（PAH）中使用整合的多组学方法。候选人目前 在大卫格芬医学院的肺部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治疗， 通过对致病机制的深入了解。在导师曼苏尔博士的指导下 Eghbali和Xia Yang，候选人将在综合系统中开发独特的跨学科技能， 单细胞，空间和实验生物学，这将有助于他在该领域的研究独立过渡 的PAH。 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， 生命，以及长期的预后。利用一个强大的队列整合最新的组学和 迫切需要计算方法来识别PAH肺中的候选分子驱动因素， 治疗目标通过对人类PAH和对照肺最大生物库的RNA测序， 通过共表达网络分析，我们鉴定了一个由266个基因组成的模块（我们将其称为 作为“粉红色”模块），其与PAH肺强烈相关。通过与右心的多模态整合 导管数据，组织学分析和全基因组关联研究（GWAS），我们发现粉红色 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） 在肺血管细胞中失调，2）在与肺血管重塑相关的途径中富集 例如内皮-间充质转化和Wnt信号传导，3）并且可以是 PAH，如ANTXR 1，一种与各种癌症密切相关的整合素样糖蛋白，但从未在 呸。鉴于大量肺源性粉红模块重要性的初步证据越来越多， 需要研究其在PAH发病机制中的细胞特异性作用， PAH肺的分子驱动因素，并确定新的治疗靶点。我们假设粉红色的模块 PAH通过肺血管细胞内的调节异常导致血管重塑。为了验证这个假设， 我们将1）使用单个- 核RNAseq和空间转录组学，以及2）确定粉红色模块的体外敲低的影响 PAH肺血管细胞中的候选驱动基因，如ANTXR 1。拟议的研究将利用一个 结合尖端的多组学方法和实验生物学，以提供更深入的了解， 一个新的PAH相关基因集来自一个大型的肺生物库，并将为我自己的实验室提供基础 和未来的R 01，将侧重于基本的机制和翻译的研究。