Identifying Protein-Protein Network Interactions between COPD Susceptibility Genes
Identifying Protein-Protein Network Interactions between COPD Susceptibility Genes
批准号:
10543862
负责人:
Edwin K Silverman
金额:
$79.47万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-01 至 2024-12-31
关键词:
AddressAffinity ChromatographyAlveolar MacrophagesBiologicalBiological AssayBiological ProcessBronchoscopyCRISPR/Cas technologyCell AgingCell DeathCell Death ProcessCell LineCellsChronic Obstructive Pulmonary DiseaseClustered Regularly Interspaced Short Palindromic RepeatsCo-ImmunoprecipitationsComplexDataDatabasesDiseaseDisease susceptibilityEpithelial CellsExcisionFutureGene SilencingGenesGenetic DeterminismGenetic DiseasesGenetic Predisposition to DiseaseGenomic SegmentHumanInflammationLaboratoriesLinkLungMass Spectrum AnalysisMethodsMicrofibrilsMinorityModelingMolecularMusMutationNetwork-basedPathogenesisPathway interactionsPhenotypeProteinsPublic HealthPulmonary EmphysemaResearchSamplingStructure of parenchyma of lungSusceptibility GeneTGFB2 geneTissue-Specific Gene ExpressionTrans-Omics for Precision MedicineTransforming Growth Factor Beta 2Transforming Growth Factor betabronchial epitheliumcell typecigarette smokingdisorder riskeffective therapyexperimental studyexposure to cigarette smokeextracellulargene interactiongene networkgene productgenome wide association studygenomic locusinnovationinsightinterestnovelprotein protein interactiontranscriptome sequencingtranscriptomics
中文摘要
项目总结
像COPD这样的复杂疾病的全基因组关联研究(GWAS)已经确定了许多基因组
与疾病相关的区域,但这些遗传位点影响疾病的分子机制
发病机制很大程度上还不清楚。基因改变的表型效应可能是由于
蛋白质之间的协调相互作用。然而,COPD Gwas基因座中的关键基因只有
在这些COPD GWA区中的少数区域被证实,以及COPD GWA区基因之间的网络连接
产品很少被识别出来。在这个项目中,我们将利用两者支持的COPD易感基因
GWAS和小鼠肺气肿模型开发细胞类型特异性和疾病特异性蛋白-蛋白
与慢性阻塞性肺疾病相关的互动网络模块。我们假设构建疾病网络模块是基于
实验验证的COPD基因之间的蛋白质-蛋白质相互作用将识别新的生物
影响细胞死亡、细胞衰老和/或COPD相关疾病过程的联系
发炎。我们将进行亲和纯化/质谱分析(AP-MS)九个成熟的
慢性阻塞性肺疾病基因产物。作为慢性阻塞性肺疾病基因间网络链接一部分的相互作用蛋白
在AP-MS分析的基础上,将用免疫共沉淀分析进一步验证。我们将利用疾病
将新的AP-MS实验与现有分子相结合的网络模块构建方法
相互作用的数据,以寻找慢性阻塞性肺疾病基因产物之间的生物联系。我们将确定细胞类型-
基于RNA-Seq数据去除未表达基因的特定蛋白质-蛋白质相互作用网络
支气管上皮细胞和肺泡巨噬细胞以及疾病特异性蛋白质-蛋白质相互作用网络
基于来自肺组织研究联盟的肺组织的TOPMed RNA-Seq数据。对于网络路径
将COPD基因连接到蛋白质-蛋白质相互作用网络中,我们将扰乱疾病网络模块
使用CRISPR-CAS9方法的组件。首先,我们将评估这些扰动对蛋白质的影响
推测的疾病网络路径的相互作用。其次,我们将评估这些网络节点移除的影响
对基于细胞的COPD相关读数的扰动,包括细胞死亡、细胞衰老和炎症。
细胞系实验中的阳性表型读数将在原代人类肺细胞中得到验证。这个项目
将结合最先进的计算和实验室方法来识别蛋白质-蛋白质相互作用
不同肺细胞类型中COPD基因间的网络关系及验证
使用基于细胞的相关生物过程读数与COPD发病机制的关系。
英文摘要
PROJECT SUMMARY
Genome-wide association studies (GWAS) of complex diseases like COPD have identified many genomic
regions associated with disease, but the molecular mechanisms by which these genetic loci influence disease
pathogenesis are largely unknown. The phenotypic effects of genetic alterations can result from disruptions of
the coordinated interactions between proteins. However, the key genes within COPD GWAS loci have only been
proven in a minority of those COPD GWAS regions, and network connections between the COPD GWAS gene
products have rarely been identified. In this project, we will utilize COPD susceptibility genes supported by both
GWAS and murine emphysema models to develop cell type-specific and disease-specific protein-protein
interaction network modules related to COPD. We hypothesize that building disease network modules based on
experimentally validated protein-protein interactions between COPD GWAS genes will identify novel biological
connections that influence COPD-related disease processes of cell death, cellular senescence, and/or
inflammation. We will perform affinity purification/mass spectrometry (AP-MS) assays of nine well-established
COPD GWAS gene products. Interacting proteins that are part of network links between COPD GWAS genes
based on the AP-MS assays will be further validated with co-immunoprecipitation assays. We will utilize disease
network module building approaches that combine the new AP-MS experiments with existing molecular
interactome data to find biological linkages between COPD GWAS gene products. We will identify cell type-
specific protein-protein interaction networks by removing non-expressed genes based on RNA-Seq data in
bronchial epithelial cells and alveolar macrophages, and disease-specific protein-protein interaction networks
based on TOPMed RNA-Seq data from lung tissue in the Lung Tissue Research Consortium. For network paths
linking COPD GWAS genes in the protein-protein interaction network, we will perturb disease network module
components using CRISPR-Cas9 approaches. First, we will assess the effects of these perturbations on protein
interactions of putative disease network paths. Second, we will assess the impact of these network node removal
perturbations on cell-based COPD-related readouts, including cell death, cellular senescence, and inflammation.
Positive phenotypic readouts in cell line experiments will be validated in primary human lung cells. This project
will combine state-of-the-art computational and laboratory approaches to identify the protein-protein interaction
network relationships between COPD GWAS genes within multiple lung cell types and to validate those network
relationships using cell-based readouts of relevant biological processes for COPD pathogenesis.
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会议论文
Identifying Protein-Protein Network Interactions between COPD Susceptibility Genes
-
批准号:10323060
-
项目类别:
-
资助金额:$79.47万
-
财政年份:2021
-
负责人:Edwin K Silverman
-
依托单位:
Functional Genomic Approaches to Dissect COPD GWAS Loci
-
批准号:9025972
-
项目类别:
-
资助金额:$61.91万
-
财政年份:2014
-
负责人:Edwin K Silverman
-
依托单位:
Functional Genomic Approaches to Dissect COPD GWAS Loci
-
批准号:8607362
-
项目类别:
-
资助金额:$25.58万
-
财政年份:2014
-
负责人:Edwin K Silverman
-
依托单位:
Functional Genomic Approaches to Dissect COPD GWAS Loci
-
批准号:8803806
-
项目类别:
-
资助金额:$22.22万
-
财政年份:2014
-
负责人:Edwin K Silverman
-
依托单位:
SYSTEMS GENETICS AND GENOMICS OF LUNG DISEASES
-
批准号:9315198
-
项目类别:
-
资助金额:$34.29万
-
财政年份:2013
-
负责人:Edwin K Silverman
-
依托单位:
SYSTEMS GENETICS AND GENOMICS OF LUNG DISEASES
-
批准号:8575264
-
项目类别:
-
资助金额:$12.42万
-
财政年份:2013
-
负责人:Edwin K Silverman
-
依托单位:
SYSTEMS GENETICS AND GENOMICS OF LUNG DISEASES
-
批准号:8722621
-
项目类别:
-
资助金额:$27.0万
-
财政年份:2013
-
负责人:Edwin K Silverman
-
依托单位:
Integrating Omics, Networks, and Functional Studies in COPD and IPF
-
批准号:10636906
-
项目类别:
-
资助金额:$49.76万
-
财政年份:2013
-
负责人:Edwin K Silverman
-
依托单位:
Integrating Omics, Networks, and Functional Studies in COPD and IPF
-
批准号:10172314
-
项目类别:
-
资助金额:$37.98万
-
财政年份:2013
-
负责人:Edwin K Silverman
-
依托单位:
Functional Genetics of COPD
-
批准号:8179032
-
项目类别:
-
资助金额:$267.3万
-
财政年份:2011
-
负责人:Edwin K Silverman
-
依托单位:
Functional Genetics of COPD
-
批准号:8321906
-
项目类别:
-
资助金额:$253.6万
-
财政年份:2011
-
负责人:Edwin K Silverman
-
依托单位:
Functional Genetics of COPD
-
批准号:8501655
-
项目类别:
-
资助金额:$232.5万
-
财政年份:2011
-
负责人:Edwin K Silverman
-
依托单位:
Functional Genetics of COPD
-
批准号:8685304
-
项目类别:
-
资助金额:$235.01万
-
财政年份:2011
-
负责人:Edwin K Silverman
-
依托单位:
UNCLASSIFIED SPIROMETRIC ABNORMALITIES: RADIOLOGY, EPIDEMIOLOGY, AND GENETICS
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批准号:7935444
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项目类别:
-
资助金额:$48.46万
-
财政年份:2009
-
负责人:Edwin K Silverman
-
依托单位:
UNCLASSIFIED SPIROMETRIC ABNORMALITIES: RADIOLOGY, EPIDEMIOLOGY, AND GENETICS
-
批准号:7824754
-
项目类别:
-
资助金额:$49.99万
-
财政年份:2009
-
负责人:Edwin K Silverman
-
依托单位:
Genetic Determinants of COPD in Diverse Ethnic Groups
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批准号:7321204
-
项目类别:
-
资助金额:$77.55万
-
财政年份:2007
-
负责人:Edwin K Silverman
-
依托单位:
Genetic Epidemiology of COPD
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批准号:7502748
-
项目类别:
-
资助金额:$89.28万
-
财政年份:2007
-
负责人:Edwin K Silverman
-
依托单位:
Genetic Determinants of COPD in Diverse Ethnic Groups
-
批准号:7662292
-
项目类别:
-
资助金额:$56.24万
-
财政年份:2007
-
负责人:Edwin K Silverman
-
依托单位:
(2 of 2) Genetic Epidemiology of COPD
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批准号:9765364
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项目类别:
-
资助金额:$253.83万
-
财政年份:2007
-
负责人:Edwin K Silverman
-
依托单位:
(2 of 2) Genetic Epidemiology of COPD
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批准号:9981769
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项目类别:
-
资助金额:$236.53万
-
财政年份:2007
-
负责人:Edwin K Silverman
-
依托单位:
海外基金