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：
10476752
负责人：
ROBERT A. LAFYATIS
金额：
$ 6.94万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476752
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 Cutaneous sclerosis Data Dermal Development Disease Disease Pathway Distal Endothelial Cells Endothelium Fibroblasts Fibrosis Fumarates Gene Expression Gene Proteins Genes Goals Grant Heterogeneity Human ITGA11 gene In Vitro Integrins Interstitial Lung Diseases Lead Leukocytes Lung Lung Transplantation Lung diseases Mediating Mediator of activation protein Medical center Mesenchymal Mesenchymal Stem Cells 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 Ubiquitin Universities Vascular Endothelial Cell Vasodilator Agents Work bioinformatics network biological adaptation to stress collaborative environment data integration design disorder subtype drug development experience gene discovery genetic regulatory protein human tissue inhibitor/antagonist innovation large datasets medical schools multicatalytic endopeptidase complex novel novel therapeutics predicting response predictive marker progenitor programs pulmonary arterial hypertension pulmonary artery endothelial cell repository single-cell RNA sequencing skin disorder skin fibrosis targeted treatment therapeutically effective tool transcriptome transcriptome sequencing translational genomics translational medicine translational model translational study ubiquitin ligase ubiquitin-protein ligase 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, 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：通过转化了解致病途径研究、开发 SSc 生物标志物、开发新疗法以及应用生物信息学和解释翻译和生物标志物数据的系统生物学方法。目前的障碍之一为 SSc 患者寻找新药的进展在于对 SSc 发病机制的了解仍然有限疾病的发生，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。匹兹堡大学医学中心和波士顿大学医学中心的创新方案获得 SSc 皮肤和肺部生物样本将使研究人员能够发现基因、调节蛋白、促进 SSc 患者纤维化和血管损伤的介质和细胞。其中包括非常大的、纵向临床生物样本库； SSc肺移植和温尸检项目；和皮肤活检、离体肺灌注、功能性远端肺动脉肌电图和肺外植体培养协议。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 分析正常和 SSc 皮肤的间充质细胞异质性，并研究阻断与肌成纤维细胞分化相关的基因。在项目 2 中，调查人员将检查改变的 SSc白细胞和肺血管内皮细胞氧化应激和线粒体自噬的标志物在右心导管插入术中和从 SSc 患者的肺动脉解剖中获得相关肺动脉高压。他们还将调查最近批准的 Nrf2 的效果富马酸二甲酯对这些系统中内皮细胞的抑制剂。在项目 3 中，研究人员将研究泛素连接酶在 SSc 相关间质性肺疾病 (SSc-ILD) 中的表达。他们还会设计使用定量结构-活性关系确定 SSc-ILD 的最佳泛素连接酶拮抗剂，并进行测试这些抑制剂在肺外植体和离体肺灌注模型中的作用。项目目标将得到三个方面的支持资源核心：临床和生物样本核心、肺组织核心和转化基因组学和数据集成核心。后者将综合来自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。各有侧重关于不同 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，用于桥接项目主题和核心的基础发现资源。该项目和核心的互补经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，最终开发出新的靶向疗法。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.

人抗干扰素α受体单克隆抗体 MEDI-546 在系统性硬化症受试者中的剂量递增：一项 1 期、多中心、开放标签研究。

DOI：
发表时间：
2014-02-24
期刊：
影响因子：
4.9
作者：
Goldberg, Avram;Geppert, Thomas;Schiopu, Elena;Frech, Tracy;Hsu, Vivien;Simms, Robert W;Peng, Stanford L;Yao, Yihong;Elgeioushi, Nairouz;Chang, Linda;Wang, Bing;Yoo, Stephen
通讯作者：
Yoo, Stephen

Relation of novel echocardiographic measures to invasive hemodynamic assessment in scleroderma-associated pulmonary arterial hypertension.

硬皮病相关肺动脉高压的新型超声心动图测量与侵入性血流动力学评估的关系。

DOI：
发表时间：
2014-09
期刊：
影响因子：
4.7
作者：
Gopal, Deepa M;Doldt, Bryan;Finch, Kim;Simms, Robert W;Farber, Harrison W;Gokce, Noyan
通讯作者：
Gokce, Noyan

Myofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin.

肌成纤维细胞转录组表明系统性硬化症皮肤中存在 SFRP2hi 成纤维细胞祖细胞。

DOI：
发表时间：
2021
期刊：
影响因子：
16.6
作者：
Tabib, Tracy;Huang, Mengqi;Morse, Nina;Papazoglou, Anna;Behera, Rithika;Jia, Minxue;Bulik, Melissa;Monier, Daisy E;Benos, Panayiotis V;Chen, Wei;Domsic, Robyn;Lafyatis, Robert
通讯作者：
Lafyatis, Robert

Bloodstream infections in patients with pulmonary arterial hypertension treated with intravenous prostanoids: insights from the REVEAL REGISTRY®.

接受静脉注射前列腺素治疗的肺动脉高压患者的血流感染：来自 REVEAL REGISTRY® 的见解。

DOI：
发表时间：
2012-09
期刊：
影响因子：
8.9
作者：
Kitterman, Natalie;Poms, Abby;Miller, Dave P;Lombardi, Sandra;Farber, Harrison W;Barst, Robyn J
通讯作者：
Barst, Robyn J

TRPV4 ION Channel Is Associated with Scleroderma.

TRPV4 离子通道与硬皮病有关。

DOI：
发表时间：
2017-04
期刊：
影响因子：
0
作者：
Goswami, Rishov;Cohen, Jonathan;Sharma, Shweta;Zhang, David X;Lafyatis, Robert;Bhawan, Jag;Rahaman, Shaik O
通讯作者：
Rahaman, Shaik O