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

• 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
• 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

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物工具和其他翻译 研究观察，以发现系统性硬化症(SSC)患者的新疗法。这个目标可以是 分为四个中间目标：通过翻译研究了解致病途径， 应用生物信息学和系统生物学确定SSc并发症的信息生物标志物 解释翻译和生物标记物数据的方法，并开发新的靶向疗法。其中 目前在为SSc患者寻找新药方面取得进展的障碍是对 SSc的发病机制，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 模特们。匹兹堡大学医学院在信息性翻译方面处于独特的地位 由于特殊的资源和智力，对SSC的研究。它有非常大的，纵向的临床生物学 风湿科和肺科的SSC储存库；它拥有唯一的大型国家经验 SSC皮肤和肺的细胞研究；它在研究肺蛋白质组学方面有丰富的经验；它有肺 使用体外精确切割肺切片和体外肺灌流来模拟肺部疾病的专家；它具有 研究儿科局限性硬皮病以及儿科SSC的高度复杂的程序；它有一个 经验丰富、勇于创新的系统生物学团队；并拥有蓬勃发展的药物发现平台。在项目1中 研究人员将使用单细胞rna-seq来扩展初步观察，以了解转录。 肌成纤维细胞分化相关因子及潜在因子/细胞因子的发现 SSC和儿童LS中巨噬细胞-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 和SSc相关性间质性肺病患者的蛋白质组图谱。《项目2》也将上映 并使用精密切割的肺切片开展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相关性肺动脉高压中的作用。 AIMS项目将得到两个资源核心的支持：一个临床和生物学家核心和一个系统生物学 核心。前者将包括收集全面的临床资料、获取皮肤活检和肺移植。 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 检测立体特异性转铁蛋白结合位点和发现潜在的细胞介导性因子的新方法 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，并集成来自每个项目和跨项目的数据以开发 常见的分子通路与不同的疾病表现相关联。每一场比赛的焦点 关于不同SSC临床表现、疾病介体和药物抑制物的项目将提供丰富的、 在项目主题和核心资源之间建立高度协作的基础发现环境。