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/文摘