Targeting the Apoptosis-Resistant Pulmonary Myofibroblast

描述（由申请人提供）：特发性肺纤维化（Idiopathic pulmonary fibrosis， IPF）是一种发病率和死亡率不断上升的无法治愈的致命疾病。尽管最近有协调的尝试将体外和临床前模型验证的发现迅速转化为生物学上有希望的干预措施，但尚未取得重大的治疗突破。具有纤维化特征的破坏性重塑的最后一种常见途径是抗凋亡的肌成纤维细胞，它既能产生介质和基质微环境的改变，也能对其作出反应，从而使纤维形成持续下去。停止肌成纤维细胞表型的发展，或一旦建立逆转它，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，作为细胞表型的环境依赖性调节因子，在成纤维细胞灶内的肌成纤维细胞中沉默，成纤维细胞灶是IPF的标志性组织病理病变，其存在预示着预后不良。培养的肺成纤维细胞中缺乏Thy-1可促进细胞增殖、细胞因子和生长因子的表达和反应性、迁移、肌成纤维细胞分化和对细胞凋亡的抵抗，这些均可在Thy-1的重新表达后逆转。它们-1在细胞表面与α v整合素和syndecan 4相互作用，调节细胞-细胞和细胞-基质相互作用

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.