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

• 批准号: 10705660
• 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
• 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/10705660
• 关键词: 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; 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; Genetic; Genome; Genomics; Goals; Histologic; Human; Immune; Inflammation; Interstitial Lung Diseases; Longitudinal cohort; Lung; Lung diseases; MADH3 gene; Maps; Mass Spectrum Analysis; Mediating; Mediator; Medical; Medicine; Mesenchymal; Methods; Minority; Modality; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Myofibroblast; Network-based; Nonspecific Interstitial Pneumonia; Nuclear; Organ; PIK3CG gene; 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; biological systems; biomarker identification; cell type; clinical translation; diagnostic biomarker; drug candidate; drug development; epigenomics; human tissue; idiopathic pulmonary fibrosis; improved; inhibitor; innovation; insight; middle age; mortality; multiple omics; neural network; new technology; 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; vascular injury

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）的肺部受累很常见，比其他结缔组织疾病更常见。 组织疾病，是其主要死因，表现为间质性肺病（ILD）或肺 动脉高血压（PAH）。只有两种食品药品监督管理局（FDA）批准的化合物（尼达尼布 和托珠单抗）已被证明可以减缓SSc-ILD患者的肺功能下降，但不能阻止或逆转 SSc-ILD进展。这突出了对改善SSc的分子理解的未满足的医学需求。 ILD发病机制，用于确定药物开发的新靶点。SSc-ILD被认为是由以下因素触发的： 免疫介导的微血管损伤，诱导并维持炎症、自身免疫反应， 成纤维细胞到肌成纤维细胞的活化，随后胶原沉积，最终导致肺纤维化。我们 最近提供了人类和小鼠中已知最大的肺蛋白质组，包括8000多个 蛋白质，发现新的药物介质和细胞类型驱动肺纤维化。我们发现了几个 共有的纤维化介质（例如，SMAD 3/TGF-β通路）。 然而，SSc肺蛋白质组的准确定量和表征仍有待进行。 利用新的技术进步，我们建议定义和量化纤维化的复杂组成， SSc肺，并发现肺蛋白质组中将作为外周生物标志物和/或药物的组分 用于监测和治疗SSc-ILD的候选人。此应用程序的首要目标是 1)最详细地定义SSc-ILD肺和外周血的分子组成，2） 鉴定新疾病特异性网络模块和组织纤维化机制以改进药物 开发，以及3）发现可用作诊断、预后或预测的蛋白质 SSC-ILD的生物标志物。我们假设SSc肺蛋白质组识别SSc特异性药物线索， 由原纤维细胞产生，导致持续的肺纤维化。我们将定义和量化 与疾病相关的SSc-ILD患者肺和血液蛋白质组的组成 SSc-ILD患者横断面和纵向队列的严重程度。我们将提供SSc-ILD肺的 表观遗传景观和转录组在单细胞分辨率通过执行基因表达和开放 使用Chromium单多组ATAC +细胞核中的基因组表达分析的染色质可及性测定 肺细胞悬液的制备。最后，我们将使用一种新型的药物筛选平台TGF-β， 诱导Ssc衍生的原代成纤维细胞中的Smad易位，并表征该类抑制剂 III磷脂酰肌醇-3-激酶（PI 3 K）空泡蛋白分选34（Vps 34）作为新的靶点， 抑制肺纤维化。我们将与其他CORT核心和项目密切合作以生成新数据 关于SSc-ILD的常见和特定驱动因素，以确定 SSc-ILD中纤维化途径的病理生物学。