Targeting the Apoptosis-Resistant Pulmonary Myofibroblast

靶向抗凋亡肺肌成纤维细胞

• 批准号: 8371194
• 负责人: James S. Hagood
• 金额: $ 38.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371194
• 关键词: Adhesions; Animal Model; Apoptosis; Apoptotic; Biology; Bleomycin; Cell Survival; Cell surface; Cells; Cessation of life; Cicatrix; Coupling; Data; Development; Disease; Fibroblasts; Fibrosis; Focal Adhesion Kinase 1; Growth Factor; Hamman-Rich syndrome; Heterogeneity; Histologic; Human; In Vitro; Incidence; Individual; Integrins; Intervention; Knowledge; Laboratories; Lesion; Lung; Lung diseases; Mechanics; Mediating; Mediator of activation protein; Membrane Glycoproteins; Membrane Microdomains; Modeling; Molecular; Mus; Muscle; Myofibroblast; Pathogenesis; Pathway interactions; Phenotype; Pre-Clinical Model; Proteins; Reporting; Resistance; Rodent; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Transforming Growth Factor beta; Translating; Translations; Tumor Suppressor Proteins; Work; base; cytokine; fibrogenesis; improved; in vivo; in vivo Model; innovation; migration; mortality; mouse model; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; src-Family Kinases; syndecan-4; transcription factor

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an incurable fatal disease with increasing incidence and mortality. Despite recent coordinated attempts to rapidly translate findings which have been validated in vitro and in preclinical models into biologically promising interventions, there have been no major therapeutic breakthroughs. A final common pathway for the destructive remodeling which characterizes fibrosis is the apoptosis-resistant myofibroblast, which both creates and responds to an altered mediator and matrix microenvironment, thus perpetuating fibrogenesis. Halting the development of the myofibroblast phenotype, or reversing it once established, offers the best hope of successfully treating IPF. The cell surface glycoprotein Thy-1, a known tumor suppressor which acts as a context-dependent regulator of cell phenotype, is silenced in the myofibroblasts within fibroblastic foci, the signature histopathologic lesions in IPF, the presence of which portends a poor prognosis. Absence of Thy-1 in cultured lung fibroblasts promotes proliferation, cytokine and growth factor expression and responsiveness, migration, myofibroblastic differentiation, and resistance to apoptosis, all reversible upon re-expression of Thy-1. Thy-1 interacts with alpha v integrins and syndecan 4 at the cell surface, modulating cell-cell and cell-matrix interactions and mechanical coupling, to inhibit TGF-beta activation and myofibroblastic differentiation. The effects of Thy-1 on the myofibroblast phenotype are broad, including: decreased expression of a number of muscle-specific proteins and myogenic transcription factors, inhibition of contractility, and promotion of apoptosis. Furthermore, some of the functions of Thy-1 can be recapitulated by the administration of soluble Thy-1, and preliminary data demonstrate that soluble Thy-1 reverses established fibrosis in a mouse model, indicating that Thy-1 itself can be used or modified for therapeutic benefit. Taken together, this knowledge leads us to the overall hypothesis that Thy-1-mediated signaling broadly suppresses myofibroblastic transformation and promotes apoptosis, restoring homeostatic function in lung fibroblasts. Improved understanding of the molecular mechanisms involved will uncover novel strategies for reversing the pathogenic myofibroblast phenotype in IPF and other fibrotic disorders. In vitro and in vivo models based on heterogeneity and targeted disruption of Thy-1 offer excellent opportunities for defining myofibroblast-targeting strategies, as outlined in the following specific aims: Aim 1: To define the mechanisms by which Thy-1- inhibits myofibroblastic differentiation of lung fibroblasts; Aim 2: To define the mechanisms by which Thy-1 promotes myofibroblast apoptosis; and Aim 3: To harness Thy-1-modulated signaling to reverse the apoptosis-resistant myofibroblast phenotype in vivo. Significance: Because Thy-1 modulates multiple signaling pathways critical to fibrogenesis, capitalizing on its function is more attractive than targeting a single pathway, which has been shown to be an ineffective approach in IPF. The proposed studies will thus define mechanisms by which Thy-1 suppresses profibrotic differentiation of lung fibroblasts, and translate that knowledge into innovative therapeutic interventions for fibrotic lung disease. PUBLIC HEALTH RELEVANCE: Targeting individual signaling pathways has failed time and again in treating idiopathic pulmonary fibrosis (IPF), a fatal and progressive lung disease which is increasing in incidence. The differentiation of a structural cell in the lung known as the fibroblast into the aggressive scar-forming myofibroblast, which resists programmed cell death (apoptosis) and gradually replaces the lung with scar tissue, is central to the pathogenesis of IPF. Restoring or replacing the function of Thy-1, a fibroblast molecule that globally suppresses the apoptosis-resistant myofibroblast phenotype, offers the best hope for treating this devastating disease.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种无法治愈的致命疾病，其发病率和死亡率不断增加。尽管最近进行了协调一致的尝试，试图将在体外和临床前模型中得到验证的发现快速转化为具有生物学前景的干预措施，但尚未取得重大的治疗突破。以纤维化为特征的破坏性重塑的最后一个共同途径是抗凋亡肌成纤维细胞，它会产生并响应改变的介质和基质微环境，从而使纤维化永久化。阻止肌成纤维细胞表型的发展，或一旦建立就逆转它，为成功治疗 IPF 提供了最大的希望。细胞表面糖蛋白 Thy-1 是一种已知的肿瘤抑制因子，可作为细胞表型的环境依赖性调节剂，在成纤维细胞病灶内的肌成纤维细胞中被沉默，这是 IPF 的标志性组织病理学病变，其存在预示着不良预后。培养的肺成纤维细胞中 Thy-1 的缺失会促进增殖、细胞因子和生长因子的表达以及反应性、迁移、肌纤维母细胞分化和细胞凋亡抵抗，所有这些在 Thy-1 重新表达后都是可逆的。 Thy-1 与细胞表面的 α v 整合素和多聚糖 4 相互作用，调节细胞-细胞和细胞-基质相互作用， 机械耦合，抑制 TGF-β 激活和肌纤维母细胞分化。 Thy-1 对肌成纤维细胞表型的影响是广泛的，包括：许多肌肉特异性蛋白和肌源性转录因子的表达减少、收缩性抑制、 和促进细胞凋亡。此外，Thy-1 的一些功能可以通过施用可溶性 Thy-1 来重现，初步数据表明，可溶性 Thy-1 可逆转小鼠模型中已形成的纤维化，这表明 Thy-1 本身可用于或修饰以获得治疗益处。总而言之，这些知识使我们得出一个总体假设：Thy-1 介导的信号传导广泛抑制肌成纤维细胞转化并促进细胞凋亡，恢复肺成纤维细胞的稳态功能。更好地了解所涉及的分子机制将揭示逆转 IPF 和其他纤维化疾病中致病性肌成纤维细胞表型的新策略。基于 Thy-1 异质性和靶向破坏的体外和体内模型为定义肌成纤维细胞靶向策略提供了极好的机会，如以下具体目标所述： 目标 1：确定 Thy-1- 抑制肺成纤维细胞肌成纤维细胞分化的机制；目标2：明确Thy-1促进肌成纤维细胞凋亡的机制；目标 3：利用 Thy-1 调节的信号传导来逆转体内抗凋亡肌成纤维细胞表型。意义：由于 Thy-1 调节对纤维形成至关重要的多种信号通路，因此利用其功能比靶向 单一途径，已被证明在 IPF 中是无效的方法。因此，拟议的研究将确定 Thy-1 抑制肺成纤维细胞促纤维化分化的机制，并将这些知识转化为纤维化肺病的创新治疗干预措施。 公共健康相关性：针对个体信号通路的治疗在治疗特发性肺纤维化 (IPF) 方面一次又一次失败，这是一种致命的进行性肺部疾病，发病率不断增加。肺部的一种结构细胞（称为成纤维细胞）分化为侵袭性疤痕形成肌成纤维细胞，可抵抗程序性细胞死亡（细胞凋亡）并逐渐用疤痕组织取代肺部，这是 IPF 发病机制的核心。 Thy-1 是一种成纤维细胞分子，可全面抑制抗凋亡的肌成纤维细胞表型，恢复或替换 Thy-1 的功能为治疗这种毁灭性疾病提供了最好的希望。