Chemogenomics to Identify New Molecular Targets in PF

描述(由申请人提供)： 氧化还原敏感转录因子激活蛋白-1(AP-1)与促纤维化基因表达有关，受氧化还原蛋白、巨噬细胞抑制因子(MIF)和氧化还原效应因子-1(Ref-1)的调节。转化生长因子β(TGFbeta)是呼吸道纤维化发生发展过程中的关键介质，在细胞增殖分化、细胞凋亡和细胞外基质沉积等过程中起重要作用。TGFb信号激活Smad(抗增殖/免疫抑制)和AP-1(促纤维化)转录途径。肺纤维化(PF)患者呼吸道中的转化生长因子β最初可能作为一种“修复分子”发挥作用，参与减轻最初的呼吸道炎症和组织修复。然而，随着持续的炎症反应，如在PF中可能发生的，平衡可能被改变，通过AP-1介导的转录增加，过度的ECM沉积和发展的呼吸道纤维化。通过抑制Ref-1或MIF选择性地抑制TGFbeta诱导的AP-1信号转导(不影响Smad转录)，理论上可以防止TGFbeta介导的ECM积聚和纤维化，并导致以抗增殖和免疫抑制为主的反应。在这项建议中，我们将利用一种新的化学基因组学方法来确定和验证AP-1转录和TGFb驱动的促纤维化基因表达的小分子抑制剂作为治疗PF患者的潜在疗法。我们的具体目标如下：目的1.研制抗转化生长因子β介导的肺纤维化小分子抑制剂(S)。目的：开发AP-1转录的小分子氧化还原MIF和Ref-1抑制剂。瞄准磅。目的：寻找新的小分子抑制肿瘤生长因子β基因表达的药物。目的2.观察AP-1/TGFβ抑制剂对实验性肺纤维化小鼠体内气道炎症和纤维化的影响。目的3、探讨AP-1/TGFβ抑制剂S对肺纤维化患者肺组织和呼吸道上皮细胞促性腺激素基因表达的影响。这些研究代表了利用化学基因组学来识别、开发和验证AP-1/TGFbeta驱动的促纤维化基因表达的小分子抑制剂作为治疗PF患者的新疗法的重点努力。

DESCRIPTION (provided by applicant): Activation of redox-sensitive transcription factor, activator protein-1 (AP-1) is associated with profibrotic gene expression and is regulated by redox proteins, macrophage inhibitory factor (MIF) and redox effector factor-1 (Ref-1). Transforming growth factor Beta(TGFBeta), a key mediator in the development of airway fibrosis, is important in cell proliferation and differentiation, apotosis, and deposition of ECM. TGFB signaling activates both Smad (anti-proliferative/immunosuppressive) and AP-1 (profibrotic) transcription pathways. TGFBeta in the airways of patients with pulmonary fibrosis (PF) may function initially as a "healing molecule" involved in the diminution of initial airway inflammation and in tissue repair. However, with continued inflammatory response such as may occur in PF, the balance may be shifted, via increased AP-1-mediated transcription, to excessive ECM deposition and development of airway fibrosis. Selective inhibition of TGFBeta- induced AP-1 signal transduction (without affecting Smad transcription) by inhibition of Ref-1 or MIF could theoretically prevent TGFBeta-mediated ECM accumulation and fibrosis and result in a predominantly antiproliferative, immunosuppressive response. In this proposal, we will utilize a novel chemogenomics approach to identify and validate small molecule inhibitors of AP-1 transcription and TGFB-driven profibrotic gene expression as potential therapies for PF patients. Our Specific Aims are as follows: Aim 1. To Develop Small Molecule Inhibitor(s) of TGFBeta-Mediated Pulmonary Fibrosis, Aim la. To Develop Small Molecule Redox MIF and Ref-1 Inhibitors of AP-1 Transcription. Aim lb. To Identify Novel Small Molecule Inhibitors of TGFBeta-driven Proflbrotic Gene Expression. Aim 2. To Determine the Effect of AP-1/TGFBeta Inhibitors on Airway Inflammation and Fibrosis In Vivo in Mouse Models of PF. Aim 3, To Determine the Effect of AP-1/TGFBeta inhibitor(s) on Proflbrotic Gene Expression in Lung Tissue and Airway Epithelial Cells of Patients with PF. These studies represent a focused effort using chemogenomics to identify, develop, and validate small molecule inhibitors of AP-1/TGFBeta-driven profibrotic gene expression as novel therapies in PF patients.