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: 10705585
• 负责人: ROBERT A. LAFYATIS
• 金额: $ 156.58万
• 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/10705585
• 关键词: 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; Center for Translational Science Activities; 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; Macrophage; Mediating; Mediator; Medical center; Metabolic; Metabolism; Modeling; Molecular; Multiomic Data; Myofibroblast; Observational Study; Organ; Oxidative Phosphorylation; PIK3CG gene; 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; Sclerosis; Serum Markers; Skin; Skin Tissue; Slice; Structure of parenchyma of lung; Systemic Scleroderma; Systems Biology; Talents; Technology; Testing; Tissues; Translational Research; Universities; Vacuolar Protein Sorting; biobank; bioinformatics tool; cell type; clinical translation; collaborative environment; cytokine; data integration; detection method; drug discovery; epigenomics; experience; gene discovery; genetic regulatory protein; genomic data; human disease; human tissue; imaging approach; inhibitor; innovation; 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 nucleus RNA-sequencing; 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志物工具和其他翻译工具， 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 分为四个中间目标：通过转化研究了解致病途径， 识别SSc并发症的信息生物标志物，应用生物信息学和系统生物学 解释翻译和生物标记数据的方法，以及开发新的靶向治疗方法。之间 目前，在为SSc患者寻找新药方面取得进展的障碍是对 SSc发病机制，部分原因是其复杂性和异质性，部分原因是缺乏良好的动物 模型匹兹堡大学医学院在信息翻译方面处于独特的地位。 由于特殊的资源和智力才能进入SSc学习。它具有非常大的纵向临床生物学特征， 在风湿病学和肺科的SSc知识库;它拥有唯一的大型国家经验， 在SSc皮肤和肺中进行细胞研究;它在研究肺蛋白质组学方面具有丰富的经验;它具有肺 使用体外精确切割肺切片和离体肺灌注进行肺部疾病建模的专家; 高度复杂的程序研究小儿局限性硬皮病，以及小儿SSc;它有一个 经验丰富和创新的系统生物学团队;并拥有一个充满活力的药物发现平台。项目1 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转录因子（TF），并发现潜在的因子/细胞因子介导 SSc和儿科LS中的巨噬细胞-成纤维细胞相互作用。在项目2中，研究人员将检查基因组 与Ssc相关的间质性肺病患者的蛋白质组学景观。《Project 2》也将上映 并利用精密切割的肺切片进行Smad 3易位抑制剂的临床前研究。项目3 研究人员将研究血小板能量学的改变，并利用18F-氟谷氨酰胺PET成像来了解 代谢重编程和β-内酰胺酶在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：临床和生物标本核心和系统生物学 核心前者将包括收集全面的临床数据，获取皮肤活检和肺移植 组织和制备精确切割的肺切片。后者将使用广泛的生物信息学工具，包括 用于检测立体特异性TF结合位点和用于发现介导细胞凋亡的潜在因子的新方法。 scRNA-seq/multiome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 和基因组数据，并整合来自每个项目和跨项目的数据， 与不同疾病表现相关的共同分子途径。每一个的焦点 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， 高度协作的环境，用于在桥接项目主题和核心资源中进行基本发现。

项目成果

Loss of Protein Kinase D2 Activity Protects Against Bleomycin-Induced Dermal Fibrosis in Mice.

• DOI: 10.1016/j.labinv.2022.100018
• 发表时间: 2023-02
• 期刊: LABORATORY INVESTIGATION
• 影响因子: 5
• 作者: Chen, Liping;Zhao, Jinjun;Chao, Yapeng;Roy, Adhiraj;Guo, Wenjing;Qian, Jiabi;Xu, Wanfu;Domsic, Robyn T.;Lafyatis, Robert;Lu, Binfeng;Deng, Fan;Wang, Q. Jane
• 通讯作者: Wang, Q. Jane