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From proteomics and genomics to therapeutics in systemic sclerosis interstitial lung disease

从蛋白质组学和基因组学到系统性硬化症间质性肺病的治疗

基本信息

批准号：
10404144
负责人：
Oliver Eickelberg
金额：
$ 29.83万
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：
2022-09-20 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10404144
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Area Autoimmune Autoimmune Responses Automobile Driving Biological Assay Biological Markers Biology Blood Blood Proteins Blood Vessels Cause of Death Cell Communication Cells Chromatin Chromium Clinical Collagen Connective Tissue Diseases Coughing Cues Data Deposition Disease Disease Progression Drug Screening Drug usage Effector Cell Epigenetic Process Etiology Exhibits Extracellular Matrix Fibroblasts Fibrosis Gene Expression Genome Genomics Goals Histologic Human Immune Inflammation Injury Interstitial Lung Diseases Longitudinal cohort Lung Lung diseases MADH3 gene Maps Mass Spectrum Analysis Mediating Mediator of activation protein Medical Medicine Mesenchymal Methods Minority Modality Modeling Molecular Monitor Morbidity - disease rate Mus Myofibroblast Network-based Nonspecific Interstitial Pneumonia Nuclear Pathogenesis Pathway interactions Patients Pattern Peripheral Preparation Prevalence Prognostic Marker Proteins Proteome Proteomics Pulmonary Fibrosis Raynaud Disease Resolution Scleroderma Severity of illness Skin Slice Structure of parenchyma of lung Suspensions Systemic Scleroderma Testing Therapeutic Tissues Transforming Growth Factor beta United States Food and Drug Administration Usual Interstitial Pneumonia Vacuolar Protein Sorting Vascular Diseases Woman Work XCL1 gene base biological systems cell type diagnostic biomarker drug candidate drug development epigenomics human tissue idiopathic pulmonary fibrosis improved inhibitor innovation insight middle age mortality neural network new therapeutic target nintedanib novel novel therapeutics peripheral blood predictive marker pulmonary arterial hypertension pulmonary function decline skin disorder skin lesion therapeutic target tocilizumab trait transcriptome transcriptomics translational study

项目摘要

Lung involvement in systemic sclerosis (SSc) is common, occurs more frequently in SSc than in other connective tissue diseases and is its leading cause of death, manifesting as interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH). Only two Food and Drug Administration (FDA)-approved compounds (nintedanib and tocilizumab) have been shown to slow the decline of lung function in SSc-ILD, but do not stop or reverse the progression of SSc-ILD. This highlights an unmet medical need for improved molecular understanding of SSc- ILD pathogenesis for identification of novel targets for drug development. SSc-ILD is thought to be triggered by immune-mediated microvascular injuries that induce and perpetuate inflammation, autoimmune responses, and fibroblast-to-myofibroblast activation with subsequent collagen deposition ultimately leading to lung fibrosis. We have recently provided the largest known lung proteome in human and mouse, encompassing more than 8000 proteins, uncovering novel druggable mediators and cell types driving lung fibrosis. We have identified several shared mediators of fibrosis (e.g., the SMAD3/TGF-beta pathway) between SSc skin lesions and IPF lung tissue. An accurate quantification and characterization of the SSc lung proteome, however, remains to be performed. Using novel technological advances, we propose to define and quantify the intricate composition of the fibrotic SSc lung and uncover components within the lung proteome that will serve as peripheral biomarkers and/or drug candidates for the monitoring and treatment of SSc-ILD, respectively. The overarching goal of this application is 1) to define, in greatest detail, the molecular composition of the SSc-ILD lung and peripheral blood, 2) to identify novel disease-specific network modules and mechanisms of tissue fibrosis for improved drug development, and 3) to uncover proteins that can serve as diagnostic, prognostic, or predictive biomarkers for SSC-ILD. We hypothesize that the SSc lung proteome identifies SSc-specific druggable cues, produced by resident fibroblasts, that drive persistent lung fibrosis. We will define and quantify changes in the composition of the proteomes of the lung and blood of SSc-ILD patients that correlate with disease severity in cross-sectional and longitudinal cohorts of SSc-ILD patients. We will provide the SSc-ILD lung’s epigenetic landscape and transcriptome at single cell resolution by performing gene expression and open chromatin accessibility assays using Chromium single multiome ATAC + Genome Expression analysis in nuclear preparations of lung cell suspensions. Finally, we will use a novel drug screening platform of TGF-beta- induced Smad translocation in SSc-derived primary fibroblasts, and characterize inhibitors of the class III phosphatidylinositol-3-kinase (PI3K) vacuolar protein sorting 34 (Vps34) as novel targets for the inhibition of lung fibrosis. We will work closely with the other CORT cores and projects to generate novel data on common and specific drivers of SSc-ILD for the identification of new druggable targets underlying the pathobiology of fibrotic pathways in SSc-ILD.

系统性硬化症（SSc）肺部受累是常见的，SSc比其他结缔组织更常发生