Clinical-Translational Studies in Skin, Lung, and Vascular Complications in Systemic Sclerosis

系统性硬化症皮肤、肺和血管并发症的临床转化研究

基本信息

批准号：
10404139
负责人：
ROBERT A. LAFYATIS
金额：
$ 153.48万
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/10404139
关键词：
1-Phosphatidylinositol 3-Kinase Affect Animal Model Autoimmune Diseases Automobile Driving Binding Sites Bioinformatics Biological Biological Markers Biological Models Biology Biopsy Blood Blood Platelets Blood Vessels Cell Communication Cell Energetics Cells Childhood Chromatin Clinical Clinical Data Clinical Trials Complement Connective Tissue Cutaneous sclerosis Data Data Set Databases Development Disease Disease Marker Disease Pathway Epigenetic Process Fibroblasts Fibrosis Gene Expression Genomics Glutaminase Glutamine Goals Heterogeneity In Vitro Interleukin-6 Interstitial Lung Diseases Lead Localized scleroderma Lung Lung Transplantation Lung diseases Mediating Mediator of activation protein Medical center Metabolic Metabolism Methods Modeling Molecular Myofibroblast Observational Study Organ Oxidative Phosphorylation Pathogenesis Pathogenicity Pathologic Processes Pathway interactions Patients Perfusion Pharmaceutical Preparations Phenotype Population Positioning Attribute Positron-Emission Tomography Process Proteomics Protocols documentation Pulmonary Fibrosis Research Personnel Resources Rheumatology Role Serum Markers Skin Skin Tissue Slice Small Nuclear RNA Structure of parenchyma of lung Systemic Scleroderma Systems Biology Talents Testing Tissues Translational Research Universities Vacuolar Protein Sorting biobank bioinformatics tool cell type collaborative environment cytokine drug discovery epigenomics experience gene discovery genetic regulatory protein genomic data human disease human tissue imaging approach inhibitor innovation macrophage medical schools multiple omics new therapeutic target novel novel marker novel therapeutics preclinical study profibrotic fibroblast programs protein expression pulmonary arterial hypertension repository single cell technology single-cell RNA sequencing skin disorder specific biomarkers targeted treatment therapeutic target tool transcription factor transcriptome transcriptomics translational study vascular injury

项目摘要

The overall goal of this Center of Research Translation is to utilize biomarker tools and other translational research observations to discover new therapies for patients with systemic sclerosis (SSc). This goal can be broken down into four intermediate objectives: understanding pathogenic pathways through translational studies, identifying informative biomarkers for SSc complications, applying bioinformatics and systems biology approaches to interpret translational and biomarker data, and developing novel targeted therapeutics. Among current obstacles to progress in finding new drugs for SSc patients is the continuing limited understanding of SSc pathogenesis, in part due to its complexity and heterogeneity, and in part due to the lack of good animal models. The University of Pittsburgh School of Medicine stands in a unique position for informative translational studies into SSc due to special resources and intellectual talent. It has very large, longitudinal clinical-biological SSc repositories in rheumatology and pulmonary divisions; it has the only large national experience in single cell studies in both SSc skin and lungs; it has a strong experience in studying lung proteomics; it has pulmonary experts in modeling lung disease using in vitro precision cut lung slices and ex vivo lung perfusion; it has a highly sophisticated program studying pediatric localized scleroderma, as well as pediatric SSc; it has an experienced and innovative systems biology group; and it has a vigorous drug discovery platform. In Project 1 investigators will expand preliminary observations using single cell RNA-seq, to understand the transcription factors (TFs) associated with myofibroblast differentiation and discover latent factors/cytokine mediating macrophage-fibroblast interaction in SSc and pediatric LS. In Project 2 investigators will examine the genomic and proteomic landscape of patients with SSc-associated interstitial lung disease. Project 2 will also screen and carry out preclinical studies of Smad3 translocation inhibitors using precision cut lung slices. In Project 3 investigators will study altered platelet energetics and utilize 18F-fluoroglutamine PET imaging to understand the role of metabolic reprogramming and glutaminolysis in SSc-associated pulmonary arterial hypertension. Project aims will be supported by two resource cores: a Clinical and Biospecimen Core and a Systems Biology Core. The former will include collecting comprehensive clinical data, acquiring skin biopsies and lung explant tissue, and preparing precision cut lung slices. The latter will use a broad range of bioinformatics tools, including novel methods for detecting stereospecific TF binding sites, and for discovering latent factors mediating cell- cell interactions in scRNA-seq/multiome datasets. The Systems Biology Core will also synthesize proteomic and genomic data in project 2, and integrate data from each project and across projects to develop models for common molecular pathways associated with different disease manifestations. The focus of each of the projects on different SSc clinical manifestations, mediators of disease, and drug inhibitors will provide a rich, highly collaborative environment for fundamental discovery within bridging project topics and core resources.

该研究翻译中心的总体目标是利用生物标记工具和其他翻译工具研究观察发现系统性硬化症（SSc）患者的新疗法。这个目标可以是分为四个中间目标：通过转化研究了解致病途径，应用生物信息学和系统生物学，识别 SSc 并发症的信息丰富的生物标志物解释翻译和生物标志物数据的方法，以及开发新的靶向治疗方法。之中目前在为 SSc 患者寻找新药方面取得进展的障碍是对以下方面的持续有限的了解 SSc发病机制部分是由于其复杂性和异质性，部分是由于缺乏良好的动物模型。匹兹堡大学医学院在信息转化方面处于独特的地位由于特殊的资源和智力才能而进入SSc。它具有非常大的、纵向的临床生物学风湿病学和肺科 SSc 知识库；拥有全国唯一大型单项比赛经验 SSc 皮肤和肺部的细胞研究；在肺蛋白质组学研究方面拥有丰富的经验；它有肺使用体外精密切割肺切片和离体肺灌注模拟肺部疾病的专家；它有一个研究儿科局限性硬皮病以及儿科 SSc 的高度复杂的项目；它有一个经验丰富、创新的系统生物学团队；它拥有一个充满活力的药物发现平台。在项目1中研究人员将使用单细胞 RNA-seq 扩大初步观察，以了解转录与肌成纤维细胞分化相关的因子（TF）并发现潜在的因子/细胞因子介导 SSc 和儿科 LS 中巨噬细胞与成纤维细胞的相互作用。在项目 2 中，研究人员将检查基因组 SSc 相关间质性肺病患者的蛋白质组学景观。项目2也将上映并利用精密切割肺切片开展Smad3易位抑制剂的临床前研究。在项目3中研究人员将研究改变的血小板能量学并利用 18F-氟谷氨酰胺 PET 成像来了解代谢重编程和谷氨酰胺分解在 SSc 相关肺动脉高压中的作用。项目目标将由两个资源核心支持：临床和生物样本核心和系统生物学核。前者将包括收集全面的临床数据、获取皮肤活检和肺外植体组织，并准备精密切割的肺切片。后者将使用广泛的生物信息学工具，包括检测立体特异性 TF 结合位点和发现介导细胞介导的潜在因子的新方法 scRNA-seq/多组数据集中的细胞相互作用。系统生物学核心还将合成蛋白质组和项目 2 中的基因组数据，并整合每个项目和跨项目的数据来开发模型与不同疾病表现相关的常见分子途径。各方面的重点关于不同 SSc 临床表现、疾病介质和药物抑制剂的项目将提供丰富的、高度协作的环境，可在桥接项目主题和核心资源中进行基础发现。