Translational studies for identifying and targeting novel pathways in systemic sclerosis pathogenesis

识别和靶向系统性硬化症发病机制新途径的转化研究

基本信息

批准号：
9370321
负责人：
ROBERT A. LAFYATIS
金额：
$ 130.93万
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：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9370321
关键词：
Academic Medical Centers Affect Animal Model Automobile Driving Autopsy Biogenesis Bioinformatics Biological Biological Markers Biological Models Biology Biopsy Blood Vessels Boston Cardiac Catheterization Procedures Catheters Cell Differentiation process Cell model Cells Cicatrix Clinical Complement Connective Tissue Data Data Set Dermal Development Disease Disease Pathway Distal Endothelial Cells Fibroblasts Fibrosis Fumarates Gene Expression Gene Proteins Genes Goals Grant Heterogeneity Human ITGA11 gene In Vitro Injury Integrins Interstitial Lung Diseases Lead Leukocytes Lung Lung Transplantation Lung diseases Mediating Mediator of activation protein Medical center Mesenchymal Messenger RNA Mitochondria Modeling Molecular Myofibroblast Myography Observational Study Organ Oxidative Stress Pain Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Patients Perfusion Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Population Population Analysis Pre-Clinical Model Prognostic Marker Proteomics Protocols documentation Pulmonary artery structure Quantitative Structure-Activity Relationship Regulation Research Personnel Resources Sampling Scientist Serum Serum Markers Signal Pathway Skin Specimen Structure of parenchyma of lung System Systemic Scleroderma Systems Biology Technology Testing Tissues Translational Research Treatment Efficacy Ubiquitin Universities Vascular Endothelial Cell Vasodilator Agents Work biological adaptation to stress collaborative environment data integration design disorder subtype drug development experience gene discovery genetic regulatory protein human tissue inhibitor/antagonist innovation medical schools multicatalytic endopeptidase complex novel novel therapeutics predicting response predictive marker progenitor programs pulmonary arterial hypertension pulmonary artery endothelial cell repository skin disorder skin fibrosis targeted treatment tool transcriptome transcriptome sequencing translational genomics translational medicine translational study ubiquitin ligase ubiquitin-protein ligase

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, developing biomarkers for SSc, developing novel therapeutics, and applying bioinformatic and systems biology approaches to interpret translational and biomarker data. Among current obstacles to progress in finding new drugs for SSc patients is the continuing limited understanding of pathogenesis of SSc disease, in part due to its complexity and heterogeneity, and in part due to the lack of good animal models. Innovative protocols of University of Pittsburgh Medical Center and Boston University Medical Center for obtaining SSc skin and lung biosamples will allow investigators to discover the genes, regulatory proteins, mediators and cells that promote fibrosis and vascular injury in SSc patients. These include very large, longitudinal clinical-biological sample repositories; SSc lung transplant and warm autopsy programs; and skin biopsy, ex vivo lung perfusion, functional distal pulmonary arterial myography and lung explant culture protocols. In Project 1 investigators will validate biomarkers of SSc skin and lung disease, investigate mesenchymal cell heterogeneity in normal and SSc skin using single cell RNA-seq, and study the effect of blocking genes associated with myofibroblast differentiation. In Project 2 investigators will examine altered markers of oxidative stress and mitophagy in SSc leukocytes and pulmonary vascular endothelial cells obtained during right heart catheterization and from dissected pulmonary arteries of patients with SSc- associated pulmonary arterial hypertension. They will also investigate the effect of the recently approved Nrf2 inhibitor, dimethyl fumarate, on endothelial cells in these systems. In Project 3 investigators will study expression of ubiquitin ligases in SSc-associated interstitial lung disease (SSc-ILD). They will also design optimal ubiquitin ligase antagonists for SSc-ILD using quantitative structure-activity relationships, and test these inhibitors in lung explant and ex vivo lung perfusion models. Project aims will be supported by three resource cores: a Clinical and Biological Specimen Core, a Lung Tissue Core and a Translational Genomics and Data Integration Core. The latter will synthesize 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. This will be further enhanced by the complementary experience of the project and core investigators in biosampling, biomarkers, translational medicine, drug development, bioinformatics and systems biology, culminating in the development of new, targeted therapeutics.

该研究中心翻译的总体目标是利用生物标志物工具和其他翻译研究发现系统性硬化症患者（SSC）的新疗法的研究观察结果。这个目标可以是分解为四个中间目标：通过翻译理解致病途径研究，为SSC开发生物标志物，开发新型治疗剂以及应用生物信息学和系统生物学方法解释转化和生物标志物数据。当前的障碍为SSC患者寻找新药物的进展是对SSC发病机理的持续有限的了解疾病，部分是由于其复杂性和异质性，部分原因是缺乏良好的动物模型。匹兹堡大学医学中心和波士顿大学医学中心的创新协议获得SSC皮肤和肺部生物样本将使研究人员发现调节蛋白的基因，促进SSC患者纤维化和血管损伤的介质和细胞。这些包括很大，纵向临床生物样品存储库； SSC肺移植和温暖的尸检计划；和皮肤活检，离体肺灌注，功能性远端肺动脉造影和肺epplant培养物协议。在项目1中，研究人员将验证SSC皮肤和肺部疾病的生物标志物，调查使用单细胞RNA-Seq在正常和SSC皮肤中的间充质细胞异质性，并研究阻断与肌纤维细胞分化相关的基因。在项目2中，调查人员将检查变更 SSC白细胞和肺血管内皮细胞中氧化应激和线索的标记从右心导管插入期间获得的SSC-患者的肺动脉相关的肺动脉高压。他们还将研究最近批准的NRF2的效果抑制剂，富马酸二甲基，在这些系统的内皮细胞上。在项目3中，调查人员将研究泛素连接酶在与SSC相关的间质肺疾病（SSC-ild）中的表达。他们还将设计使用定量的结构活性关系，用于SSC-ILD的最佳泛素连接酶拮抗剂，并测试这些抑制剂在肺部外植体和离体肺灌注模型中。项目目标将由三个支持资源核心：临床和生物学标本核心，肺组织核心和转化基因组学和数据集成核心。后者将综合每个项目和跨项目的数据，以开发与不同疾病表现相关的常见分子途径模型。每个的重点在不同SSC临床表现的项目中，疾病介质和药物抑制剂将提供在桥接项目主题和核心中，丰富的，高度协作的环境，用于基本发现资源。该项目和核心的补充体验将进一步增强这一点生物采样，生物标志物，转化医学，药物开发，生物信息学和系统生物学，最终在新的，有针对性的治疗剂的开发中。