Molecular Basis of Fibrosis: Regulation of Collagen

纤维化的分子基础：胶原蛋白的调节

基本信息

批准号：
8265712
负责人：
John Varga
金额：
$ 33.17万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-12-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8265712
关键词：
Biological Markers Biopsy Bone Marrow Case Fatality Rates Cells Cellular Stress Chronic Clinical Collagen Cutaneous Development Disease Employee Strikes Environment Extracellular Matrix Fibroblasts Fibronectins Fibrosis Generations HMGB1 gene Healed Health Histologic Hyaluronan Hyaluronic Acid Immune Immunologic Receptors In Vitro Individual Inflammation Inflammatory Injury Lead Left Leukocytes Ligands Measures Mediating Modeling Molecular Molecular Profiling Mus Natural History Natural regeneration Necrosis Organ Pathogenesis Patients Pattern Performance Post-Translational Protein Processing Process Progressive Disease Reactive Oxygen Species Receptor Activation Receptor Signaling Recurrence Refractory Regulation Research Rheumatism Role Scleroderma Severity of illness Signal Transduction Skin Sterility Stimulus Stress Systemic Scleroderma TLR4 gene Testing Therapeutic Tissues Toll-like receptors Transgenic Mice Wound Healing base biglycan cohort fibrogenesis genome-wide healing injured insight loss of function loss of function mutation microbial mouse model novel novel strategies overexpression oxidation pathogen receptor expression repaired response response to injury sensor tissue regeneration tissue repair

项目摘要

DESCRIPTION (provided by applicant): Fibrosis, the hallmark of systemic sclerosis (SSc), represents the transformation of normal wound-healing into a deregulated self-sustaining process. Recent evidence indicates that in SSc injury results in accumulation of tissue breakdown products that can be recognized as danger signals by innate immune sensors. We showed that fibroblasts express and can be activated through toll-like receptors (TLRs) in much the same way that immune cells recognize microbial pathogen-associated patterns. Furthermore,tissue expression of TLR4, and its putative endogenous ligand hyaluronic acid, are both elevated in SSc. We hpothesize that accumulation of endogenous TLR ligands in injured tissue in SSc drives TLR-mediated amplification and persistence of fibroblast activation, resulting in intractable fibrosis. In this proposal we will examine the expression, regulation and function of fibroblast TLRs in SSc. In Specific Aim 1, we will evaluate cellular TLR4 and endogenous TLR ligand levels in SSc, define a cutaneous "TLR signature", and correlate the tissue TLR signature with clinical parameters in SSc patients. In Specific Aim 2 we will examine the regulation of TLR expression, and the mechanism of TLR4-dependent fibroblast activation. In Specific Aim 3 we will examine the role of TLR4 and endogenous TLR4 ligands in scleroderma models using loss-of-function approach, and in Specific Aim 4, we will examine if fibroblast-restricted TLR overexpression can induce the transition of self-limited healing into progressive intractable fibrogenesis. These studies will provide the first insight into the role of fibroblast TLR signaling in the pathogenesis of SSc. The proposed research will accelerate the development of novel anti-fibrotic treatments for SSc. PUBLIC HEALTH RELEVANCE: Systemic sclerosis resembles uncontrolled wound healing, where healing occurs by fibrosis rather than tissue regeneration. The factors responsible for loss of regulatory mechanisms normally controlling wound healing are unknown. We propose that innate immune sensors on lesional fibroblasts are activated within the damaged tissue environment, transforming self-limited repair into intractable fibrosis. These studies will test this hypothesis. The results may elucidate novel strategies for the treatment of SSc.

描述（由申请人提供）：纤维化，系统性硬化症的标志（SSC），代表正常伤口愈合转化为放松管制的自我维持过程。最近的证据表明，在SSC损伤中会导致组织分解产物的积累，这些产品可以通过先天免疫传感器识别为危险信号。我们表明，成纤维细胞表达并可以通过Toll样受体（TLR）激活，与免疫细胞识别微生物病原体相关模式的方式几乎相同。此外，在SSC中，TLR4的组织表达及其假定的内源性配体透明质酸均升高。我们认为，在SSC中受伤的组织中内源性TLR配体的积累驱动TLR介导的扩增和成纤维细胞激活的持久性，从而导致棘手的纤维化。在此提案中，我们将研究SSC中成纤维细胞TLR的表达，调节和功能。在特定的目标1中，我们将评估SSC中的细胞TLR4和内源性TLR配体水平，定义皮肤的“ TLR特征”，并将组织TLR特征与SSC患者的临床参数相关联。在特定目标2中，我们将检查TLR表达的调节以及TLR4依赖性成纤维细胞激活的机理。在特定目标3中，我们将使用功能丧失方法研究TLR4和内源性TLR4配体在硬皮病模型中的作用，并且在特定的目标4中，我们将检查成纤维细胞限制的TLR过表达是否可以诱导自限制的愈合过渡到累进的可疗法纤维生成。这些研究将为成纤维细胞TLR信号传导在SSC发病机理中的作用提供首次见解。拟议的研究将加速SSC的新型抗纤维化处理的发展。公共卫生相关性：系统性硬化症类似于不受控制的伤口愈合，在纤维化而不是组织再生中进行愈合。导致通常控制伤口愈合的调节机制丧失的因素尚不清楚。我们建议在受损的组织环境中激活病变成纤维细胞上的先天免疫传感器，从而将自限的修复转化为可怕的纤维化。这些研究将检验这一假设。结果可以阐明用于治疗SSC的新型策略。