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

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

展开

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.

肺参与系统性硬化症（SSC）很常见，在SSC中比其他相关的肺部受累更频繁组织疾病是其主要死亡原因，表现为间质肺疾病（ILD）或肺部疾病动脉高血压（PAH）。仅两个食品和药物管理局（FDA）批准的化合物（Nintedanib）已经显示出tocilizumab）减慢了SSC-ILD中肺功能的下降，但不要停止或逆转 SSC-ILD的进展。这突出了未满足的医学需求，以提高对SSC-的分子理解 ILD发病机理，用于鉴定药物开发的新靶标。 SSC-ild被认为是由免疫介导的微血管损伤会影响和永久注射，自身免疫反应和成纤维细胞至肌纤维细胞激活，随后的胶原蛋白沉积最终导致肺纤维化。我们最近提供了人和老鼠中最大的已知肺蛋白质组，包括超过8000 蛋白质，发现新型的可药物介质和驱动肺纤维化的细胞类型。我们已经确定了几个 SSC皮肤病变和IPF肺组织之间的纤维化（例如SMAD3/TGF-BETA途径）的共享介质。然而，SSC肺蛋白质组的准确数量和表征仍有待执行。使用新颖的技术进步，我们建议定义和量化纤维化的复杂组成 SSC肺和肺部蛋白质组中的成分，将用作周围生物标志物和/或药物分别监测和治疗SSC-ILD的候选人。此应用程序的总体目标是 1）最详细地定义了SSC-ILD肺和外周血的分子组成，2）确定新型疾病特异性网络模块和组织纤维化的机制，以改善药物开发，3）发现可以用作诊断，预后或预测性的蛋白质 SSC-ILD的生物标志物。我们假设SSC肺蛋白质组确定了SSC特异性的可药物线索，由居民成纤维细胞产生，驱动持续的肺纤维化。我们将定义和量化与疾病相关的SSC-ILD患者的肺部蛋白质组织的组成和血液的组成 SSC-ILD患者的横截面和纵向人群的严重程度。我们将提供SSC-ILD肺通过执行基因表达和开放，在单细胞分辨率下在单细胞分辨率下的表观遗传景观和转录组使用铬单个多物ATAC +基因组表达分析的染色质可及性评估肺部悬浮液的制剂。最后，我们将使用TGF-Beta-的新型药物筛查平台 SSC衍生的原代成纤维细胞中诱导的SMAD易位，并表征了类的抑制剂 III磷脂酰肌醇-3-激酶（PI3K）真空蛋白排序34（VPS34）作为新的目标抑制肺纤维化。我们将与其他Cort核心和项目紧密合作，以生成新的数据关于SSC-ILD的常见驱动因素，以识别新的可药物目标 SSC-ILD中纤维化途径的病理生物学。