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）肺部受累很常见，SSc 比其他结缔组织更常见组织疾病，是其死亡的主要原因，表现为间质性肺疾病（ILD）或肺病动脉高血压 (PAH) 只有两种美国食品和药物管理局 (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 肺功能的下降，但不能阻止或逆转 SSc-ILD 的进展凸显了对提高对 SSc-ILD 分子认识的未满足的医疗需求。用于识别药物开发新靶点的 ILD 发病机制被认为是由 SSc-ILD 触发的。免疫介导的微血管损伤，诱发和延续炎症、自身免疫反应和成纤维细胞到肌成纤维细胞的活化以及随后的胶原沉积最终导致肺纤维化。最近提供了已知最大的人类和小鼠肺蛋白质组，涵盖 8000 多个蛋白质，揭示了驱动肺纤维化的新型可药物介质和细胞类型。 SSc 皮肤病变和 IPF 肺组织之间共有纤维化介质（例如 SMAD3/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 肺并揭示肺蛋白质组内的成分，这些成分将用作外周生物标志物和/或药物分别用于监测和治疗 SSc-ILD 该应用的总体目标是。 1) 最详细地定义 SSc-ILD 肺和外周血的分子组成，2) 确定新的疾病特异性网络模块和组织纤维化机制以改进药物开发，3) 发现可用作诊断、预后或预测的蛋白质 SSC-ILD 的生物标志物我们勇敢地承认 SSc 肺蛋白质组可以识别 SSc 特异性的药物线索，由常驻成纤维细胞产生，驱动持续性肺纤维化，我们将定义并量化肺纤维化的变化。 SSc-ILD 患者肺和血液蛋白质组的组成与疾病相关我们将提供 SSc-ILD 肺部的横断面和纵向队列的严重程度。通过执行基因表达和开放，以单细胞分辨率获得表观遗传景观和转录组使用 Chromium 单多组 ATAC 进行染色质可及性测定 + 核内基因组表达分析最后，我们将使用TGF-β-的新型药物筛选平台。在 SSc 衍生的原代成纤维细胞中诱导 Smad 易位，并表征该类抑制剂 III 磷脂酰肌醇-3-激酶 (PI3K) 真空蛋白分选 34 (Vps34) 作为新靶点我们将与其他 CORT 核心和项目密切合作，生成新的数据。关于 SSc-ILD 的常见和特定驱动因素，用于识别潜在的新药物靶点 SSc-ILD 纤维化途径的病理学。