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: 7116884
• 负责人: WILLIAM REED HENDERSON
• 金额: $ 59.06万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116884
• 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）：

项目成果

Fibroblast growth factor receptor-mediated activation of AKT-β-catenin-CBP pathway regulates survival and proliferation of murine hepatoblasts and hepatic tumor initiating stem cells.

• DOI: 10.1371/journal.pone.0050401
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Mavila N;James D;Utley S;Cu N;Coblens O;Mak K;Rountree CB;Kahn M;Wang KS
• 通讯作者: Wang KS

Human embryonic stem cells differentiated to lung lineage-specific cells ameliorate pulmonary fibrosis in a xenograft transplant mouse model.

• DOI: 10.1371/journal.pone.0033165
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Banerjee ER;Laflamme MA;Papayannopoulou T;Kahn M;Murry CE;Henderson WR Jr
• 通讯作者: Henderson WR Jr