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Using Integrative Genomics To Identify and Characterize Emphysema-Associated eQTL

使用综合基因组学来识别和表征肺气肿相关的 eQTL

基本信息

批准号：
10653966
负责人：
Peter Castaldi
金额：
$ 72.22万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653966
关键词：
ACVR1B gene Affect Alternative Splicing Alveolar Cell Apoptosis Base Sequence Bioinformatics Biological Assay Biology Blood Blood specimen Cell Aging Cells Chronic Obstructive Pulmonary Disease Data Disease Drug Targeting Elements Epithelial Cells FDA approved Fibroblasts Gene Expression Genes Genetic Genetic Diseases Genomics Genotype Goals Hematological Disease Human Human Genetics Inflammation Interdisciplinary Study Leadership Lung Maps Measures Methods Minority Molecular Biology Persons Phase Phenotype Play Protein Isoforms Pulmonary Emphysema Quantitative Trait Loci RNA RNA Splicing Reporter Research Research Priority Resources Role Sampling Spliced Genes Structure of parenchyma of lung TGFB2 gene Technology Testing Tissue Procurements Tissues Trans-Omics for Precision Medicine Transforming Growth Factor Beta 2 Translational Research Variant Vascular Endothelial Cell airway epithelium cell bank cell type cigarette smoke cohort differential expression disorder risk genetic variant genome wide association study genome-wide genomic locus improved lung injury mortality nanopore novel programs public health relevance transcriptome sequencing

项目摘要

Project Summary: Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disease for which new, disease-modifying treatments are desperately needed. Since drug targets supported by human genetic evidence are more likely to lead to FDA-approved treatments, functional characterization of genome- wide association study (GWAS) loci is a translational research priority. Our group has played a leading role in COPD GWAS, and the largest COPD GWAS to date has identified 82 significant loci, most of which have not been functionally characterized. In the first phase of this project, we combined emphysema GWAS results with expression quantitative trait locus (eQTL) studies, using GWAS-eQTL colocalization methods to identify COPD GWAS target genes. This approach allowed us to prioritize TGFB2 and ACVR1B for functional studies in airway epithelial cells and lung fibroblasts that identified functional variants in these loci. However, >50% of COPD GWAS loci have not yet shown strong colocalization with eQTLs, due in part to inherent limitations of eQTLs which depend on gene-level expression quantifications that do not reflect effects of alternative splicing. Alternative splicing is an important functional mechanism for GWAS loci, perhaps equally as important as eQTLs. In the next phase of this project, we propose to identify novel COPD-associated genetic variants that alter splicing (sQTLs) and characterize their isoform-specific effects. In Aim 1, we will perform genome-wide discovery of splicing QTLs (sQTLs) using two RNA-seq resources with large numbers of subjects with COPD – blood RNA-seq from 4,515 subjects in the COPDGene Study and lung RNA-seq from 1,078 subjects in the Lung Tissue Research Consortium (LTRC). Using colocalization methods, we will identify novel COPD GWAS target genes whose splicing is altered by COPD-associated genetic variants. In Aim 2, we will identify differentially expressed and differentially used isoforms in COPD using estimated isoform quantifications from short read lung tissue RNA-seq in 1,078 COPD cases and controls in the LTRC. We will then generate Oxford Nanopore Technologies (ONT) long read RNA-seq for 10 COPD GWAS genes in 80 LTRC subjects with COPD and 80 controls using a targeted enrichment approach. In Aim 3, we will combine fine mapping and functional studies to identify COPD GWAS variants that alter splicing in primary lung cells. First, we will use targeted long read RNA-seq to characterize the cell-type specific isoform profiles of COPD GWAS target genes in four primary lung cell types. We will then functionally validate fine- mapped COPD GWAS variants using splicing reporter assays, and we will characterize the effects of these variants on COPD-related cellular phenotypes in airway epithelial cells selected by genotype from the Marsico Lung Institute cell bank. Our multi-disciplinary research team has the requisite expertise in COPD genetics and genomics, molecular biology, long read sequencing, splicing and RNA biology to complete this important project to identify novel COPD GWAS target genes involved in alternative splicing.

慢性阻塞性肺疾病（COPD）是一种进行性、衰弱性疾病

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Network-based analysis reveals novel gene signatures in peripheral blood of patients with chronic obstructive pulmonary disease.

DOI：
10.1186/s12931-017-0558-1
发表时间：
2017-04-24
期刊：
Respiratory research
影响因子：
5.8
作者：
Obeidat M;Nie Y;Chen V;Shannon CP;Andiappan AK;Lee B;Rotzschke O;Castaldi PJ;Hersh CP;Fishbane N;Ng RT;McManus B;Miller BE;Rennard S;Paré PD;Sin DD
通讯作者：
Sin DD

Turning subtypes into disease axes to improve prediction of COPD progression.

将亚型转化为疾病轴以改善对慢性阻塞性肺病进展的预测。

DOI：
10.1136/thoraxjnl-2018-213005
发表时间：
2019
期刊：
Thorax
影响因子：
10
作者：
Chen,Junxiang;Cho,Michael;Silverman,EdwinK;Hokanson,JohnE;Kinney,GregL;Crapo,JamesD;Rennard,Stephen;Dy,Jennifer;Castaldi,Peter
通讯作者：
Castaldi,Peter

A Bayesian Nonparametric Model for Disease Subtyping: Application to Emphysema Phenotypes.

贝叶斯非参数模型用于疾病亚型：应用于肺气肿表型。

DOI：
10.1109/tmi.2016.2608782
发表时间：
2017-01
期刊：
IEEE transactions on medical imaging
影响因子：
10.6
作者：
Ross JC;Castaldi PJ;Cho MH;Chen J;Chang Y;Dy JG;Silverman EK;Washko GR;Jose Estepar RS
通讯作者：
Jose Estepar RS

Hepatitis C and HIV detection by blood RNA-sequencing in cohort of smokers.