Chemogenomics to Identify New Molecular Targets in PF

化学基因组学识别 PF 的新分子靶点

• 批准号: 6802325
• 负责人: WILLIAM REED HENDERSON
• 金额: $ 60.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-18 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802325
• 关键词: AP1 protein; clinical research; combinatorial chemistry; drug design /synthesis /production; drug discovery /isolation; gene expression; high throughput technology; human subject; inflammation; laboratory mouse; laser capture microdissection; microarray technology; pharmacokinetics; protein purification; pulmonary fibrosis /granuloma; respiratory disorder chemotherapy; respiratory epithelium; tissue /cell culture; transforming growth factors

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.

描述（由申请人提供）： 氧化还原敏感性转录因子激活蛋白-1（AP-1）的激活与促纤维化基因表达相关，并受氧化还原蛋白、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（TGF β）是气道纤维化发展中的关键介质，在细胞增殖和分化、细胞凋亡和ECM沉积中起重要作用。TGFB信号传导激活Smad（抗增殖/免疫抑制）和AP-1（促纤维化）转录途径。肺纤维化（PF）患者气道中的TGF β最初可能作为一种“愈合分子”发挥作用，参与减轻初始气道炎症和组织修复。然而，随着持续的炎症反应，如可能发生在PF中，平衡可能会转移，通过增加AP-1介导的转录，过度ECM沉积和气道纤维化的发展。通过抑制Ref-1或MIF选择性抑制TGF β诱导的AP-1信号转导（不影响Smad转录），理论上可以预防TGF β介导的ECM积聚和纤维化，并导致主要的抗增殖免疫抑制反应。在这项提议中，我们将利用一种新的化学基因组学方法来鉴定和验证AP-1转录和TGF β驱动的促纤维化基因表达的小分子抑制剂作为PF患者的潜在疗法。我们的具体目标如下：目标1。为了开发TGF β介导的肺纤维化的小分子抑制剂，AP-1转录抑制剂MIF和Ref-1的研究瞄准磅。鉴定TGF β驱动的促纤维化基因表达的新型小分子抑制剂。目标二。确定AP-1/TGF β抑制剂对PF小鼠模型体内气道炎症和纤维化的作用。目的3，确定AP-1/TGF β抑制剂对PF患者肺组织和气道上皮细胞中促纤维化基因表达的作用。并验证AP-1/TGF β驱动的促纤维化基因表达的小分子抑制剂作为PF患者的新疗法。