Regulation of Fibroblast Phenotype in Lung Fibrosis

肺纤维化中成纤维细胞表型的调节

• 批准号: 7824718
• 负责人: James S. Hagood
• 金额: $ 1.81万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7824718
• 关键词: Address; Adoptive Transfer; Affect; Anchorage-Independent Growth; Animal Model; Apoptotic; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Cell Adhesion; Cells; Characteristics; Cytokine Signaling; Data; Deposition; Diagnosis; Disease; Effector Cell; Epigenetic Process; Fibroblasts; Fibrosis; Figs - dietary; Glycoproteins; Growth Factor; Hamman-Rich syndrome; Human; Hypermethylation; Impaired wound healing; In Vitro; Inflammatory; Interstitial Lung Diseases; Laboratories; Lesion; Life; Link; Lung; Lung diseases; Measures; Mediating; Mediator of activation protein; Membrane; Membrane Microdomains; Membrane Proteins; Mesenchymal; Mus; Myofibroblast; Oncogenic; Patients; Peptide Hydrolases; Phenotype; Phospholipase; Property; Proteins; Regulation; Research Personnel; Role; Sampling; Signal Transduction; Signaling Molecule; Smooth Muscle Actin Staining Method; Staining method; Stains; Stimulus; Therapeutic; Time; Tissues; Transcriptional Regulation; Transforming Growth Factor beta; Transforming Growth Factors; Transplantation; Virus Diseases; Work; Wound Healing; cell type; expectation; fibrogenesis; gene repression; in vivo; inhibitor/antagonist; loss of function; lung injury; migration; mouse model; mutant; new therapeutic target; novel; peripheral blood; programs; promoter; response; src-Family Kinases; surfactant; therapeutic target; transdifferentiation

DESCRIPTION (provided by applicant): Fibroblasts mediate the abnormal tissue repair characteristic of fibrosis, but their origin in fibrotic lung remains unclear. Evidence exists for alteration of existing fibroblasts, influx of fibroblast precursors, and transdifferentiation of other cell types. Many of the fibrogenic characteristics of lung fibroblasts are regulated by expression of Thy-1, an outer membrane leaflet surface protein which modulates cell adhesion and migration via signaling alterations in lipid raft domains. Loss of Thy-1 expression is associated with oncogenic transformation and anchorage-independent growth. Our laboratory has established that absence of Thy-1 correlates with enhanced proliferative responses of lung fibroblasts to fibrogenic growth factors and altered cytokine signaling, whereas presence of Thy-1 inhibits the ability of lung fibroblasts to i) activate latent transforming growth factor-beta (TGF-(), a key fibrogenic mediator; and to ii) express alpha-smooth muscle actin. Thy-1 -/- mice develop more severe fibrotic remodeling of the lung, and fibroblasts in fibroblastic foci of idiopathic pulmonary fibrosis (IPF) are predominantly Thy-1 (-). Inflammatory signaling causes shedding of Thy-1, activation of latent TGF-(, and transformation of fibroblasts into myofibroblasts. These findings support the hypothesis that loss of fibroblast Thy-1 expression is associated with a dysfunctional, profibrotic wound healing response in the lung. Preliminary data indicate that in addition to shedding, epigenetic regulation through promoter hypermethylation is an important mechanism for inhibition of Thy-1 expression. Furthermore, the majority of lung fibrocytes (bone-marrow derived cells which differentiate into myofibroblasts) are Thy-1 (-). Taken together with our previous work, these findings suggest that the regulation of Thy-1 expression, whether by shedding, transcriptional regulation, or recruitment of Thy-1 (-) cells, may present a novel therapeutic target for fibrosis. Thus the aims of the proposed studies are to: 1. define mechanisms for and consequences of Thy-1 shedding in the context of evolving fibrogenesis; 2. determine the roles of transcriptional and epigenetic regulation of Thy-1 expression in evolving fibrogenesis; and 3. define the relationship between Thy-1 expression and influx of fibrocytes and other bone marrow-derived cells into lungs undergoing fibrogenesis. Each of these aims will be addressed in a vertically-integrated approach using in vitro studies, relevant animal models and well-characterized human samples.

描述(申请人提供)：成纤维细胞介导纤维化的异常组织修复特征，但其在纤维化肺中的起源尚不清楚。有证据表明，现有的成纤维细胞发生了改变，成纤维细胞前体细胞大量涌入，以及其他类型细胞的转分化。肺成纤维细胞的许多纤维化特性受Thy-1的表达调控，Thy-1是一种外膜小叶表面蛋白，通过脂筏结构域的信号变化来调节细胞的黏附和迁移。Thy-1表达的缺失与肿瘤转化和锚定非依赖性生长有关。我们的实验室已经证实，Thy-1的缺失与肺成纤维细胞对纤维化生长因子的增殖反应增强和细胞因子信号的改变有关，而Thy-1的存在抑制了肺成纤维细胞的能力：i)激活关键的纤维化介质潜伏的转化生长因子-β(TGF-β)；以及ii)表达α-平滑肌肌动蛋白。THY-1-/-小鼠出现更严重的肺纤维化改建，特发性肺纤维化(IPF)成纤维细胞灶中的成纤维细胞主要为Thy-1(-)。炎症信号导致Thy-1的脱落，潜伏的转化生长因子-1的激活，以及成纤维细胞向肌成纤维细胞的转化。这些发现支持这样的假设，即成纤维细胞Thy-1表达的缺失与肺功能障碍、纤维变性的伤口愈合反应有关。初步数据表明，除了脱落，通过启动子超甲基化进行的表观遗传调控是抑制Thy-1表达的重要机制。此外，大多数肺纤维细胞(分化为肌成纤维细胞的骨髓来源细胞)是Thy-1(-)。结合我们以前的工作，这些发现表明，Thy-1表达的调节，无论是通过脱落、转录调节，还是Thy-1(-)细胞的招募，可能为纤维化提供了一个新的治疗靶点。因此，本研究的目的是：1.明确Thy-1在纤维化演变过程中脱落的机制和后果；2.确定Thy-1表达的转录和表观遗传调控在纤维化演变中的作用；以及3.明确Thy-1表达与纤维细胞和其他骨髓来源细胞在纤维化形成过程中流入肺的关系。这些目标中的每一个都将通过使用体外研究、相关的动物模型和具有良好特征的人体样本以垂直整合的方法来实现。