权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Post-GWAS Functional Genomics Analysis to Define Pathogenic Mechanisms for Pulmonary Arterial Hypertension

GWAS 后功能基因组学分析确定肺动脉高压的致病机制

基本信息

批准号：
10697364
负责人：
Wei Sun
金额：
$ 16.07万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10697364
关键词：
Affinity Alleles Allelic Imbalance Animal Model Architecture Basic Science Binding Biology Blood Vessels CRISPR/Cas technology Cell Line Clinical Coupled DNA Binding DNA Sequence Alteration Data Dependence Dependovirus Development Diagnostic Disease Disease susceptibility Down-Regulation Endothelium Enterochromaffin Cells Environment Experimental Animal Model Functional disorder Future Gene Expression Genes Genetic Genetic Predisposition to Disease Genomic approach Genomics Genotype Goals Haplotypes Human Hypoxia Intervention Knockout Mice Knowledge Link Linkage Disequilibrium Lung Lung diseases Mediating Mentors Methods Molecular Molecular Target Mus Mutation Names Pathogenesis Pathogenicity Pathway interactions Patients Persons Physicians Predisposition Proteins Pulmonary Hypertension Reporting Research Research Personnel Research Project Grants Research Technics Resources Risk Role SOX17 gene Sampling Scientist Severities Single Nucleotide Polymorphism Structure of parenchyma of lung Techniques Technology Testing Training Translational Research Universities Untranslated RNA Validation Work career career development endothelial dysfunction familial hypertension functional genomics genetic association genome wide association study genomic locus genomic platform human DNA in vivo induced pluripotent stem cell insight knock-down knowledge base lung hypoxia mouse model nanoparticle nanopolymer novel overexpression pulmonary arterial hypertension pulmonary artery endothelial cell risk variant siRNA delivery skills stem cell biology transcription factor vector virulence gene

项目摘要

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is an enigmatic and morbid disease where insights are emerging regarding genetic susceptibility to disease. Genome-wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are associated with PAH risk and severity. Yet, the GWAS-reported SNPs are only tags of haplotype SNPs in linkage disequilibrium (LD). Thus, the tag SNP may simply be linked to the true disease-causing functional SNP (fSNP). GWAS also only reveal statistical associations, and it has been challenging to define the mechanisms underlying the contribution of the PAH-associated fSNPs, which are mostly located in the non-coding regions, to the pathogenesis of PAH. Using our recently developed post-GWAS functional genomics platform, I identified a non-coding fSNP rs4738801 in the genomic locus of SOX17 gene, a known endothelial effector increasingly being studied in PAH pathogenesis. I identified that the transcription factor FUBP1 binds to the rs4738801 risk allele C in an allele-imbalanced manner, with lower affinity to risk allele C than non-risk allele G, providing an underlying mechanism how this fSNP regulates the PAH pathogenic gene SOX17 and contributes to the PAH risk. FUBP1 controls PAH-associated pathophenotypes in pulmonary arterial endothelial cells (PAECs). Downregulated by the major acquired PAH trigger hypoxia, FUBP1 and its target gene SOX17 are decreased in lungs and isolated pulmonary ECs from PAH patients and mouse models. A 3.77- fold enrichment of fSNP rs4738801 risk allele C was found in patients with PAH induced by hypoxia, supporting a pathogenic mechanism of a hypoxia-sensitive pathway (FUBP1-SOX17) combined with a disease susceptible genotype (risk allele C) for clinical manifestation of this disease. Based on these data, I hypothesize that the allele-imbalanced binding of transcription factor FUBP1 to fSNP rs4738801 defines the genomic architecture contributing to the SOX17-dependent genetic susceptibility of PAH. I further postulate that the downregulation of FUBP1-SOX17 by hypoxia contributes to the acquired pathogenesis of PAH. To test this hypothesis, I propose 2 specific aims: 1) To define the allele-specific role of fSNP rs4738801 in promoting endothelial dysfunction in PAH in gene-edited iPSC-ECs and PAH patient lung tissues; and 2) To determine the role of FUBP1 in controlling SOX17 and PAH in mouse models. Accomplishing these aims will facilitate my enduing career goal of becoming an independent physician-scientist in PAH functional genomics research. Immediate scientific development objectives include: 1) To develop expertise in PAH genetics and functional genomics; 2) To develop expertise in iPSC-EC biology and CRISPR-Cas9 gene-editing techniques; and 3) To develop skills of in vivo gene expression manipulation and become proficient in the assessment of PAH in animal models. The proposed training plan will provide me with the opportunity to expand my knowledge base to include advanced research techniques in PAH pathogenesis. The resources and expertise of my mentors, contributors, and the rich research environment at the University of Pittsburgh will assure my successful transition to an independent investigator.

项目总结