Role of Wnt/b-catenin signaling in pulmonary fibrosis

描述(由申请人提供)：本提案描述了一项职业发展计划，以成为一名成功的独立研究人员，并阐明肺纤维化发展中的新分子机制。对于这项建议，首席研究人员汇集了两位领先科学家John Varga博士和Cara Gottardi博士在纤维化和WNT信号转导领域的专业知识和经验，以创造一个独特的环境，在研究肺纤维化方面提供卓越的指导。其他科学和职业建议将由一个咨询委员会提供，该委员会由西北大学肺部和危重护理医学部备受尊敬的内科科学家组成。通过各种教学和研究培训模式，该提案将发展肺细胞和分子生物学方面的专门知识，特别是与肺纤维化有关的专门知识。这项研究将首次证明β-连环蛋白信号在肺纤维化中的直接因果作用，并将剖析规范的Wnt/β-连环蛋白信号在肺成纤维细胞中的作用。在这项建议中，人肺成纤维细胞将用于体外研究，而转基因博莱霉素功能获得和丧失的模型将用于概述体内的人肺纤维化。这项建议的目的是：1)确定负调控因子Axin2丢失导致的β-catenin活性增加是否加剧了博莱霉素诱导的肺纤维化模型中的纤维化；2)确定Wnt共受体LRP5丢失导致的β-catenin活性降低是否减弱博莱霉素诱导的纤维化表型；3)确定规范的Wnt信号是否是必需的并且足以通过细胞周期蛋白D促进细胞增殖、通过MMP7迁移和转分化。这项研究的结果将首次证明规范的Wnt/β-catenin途径与肺纤维化之间的直接因果联系，并为肺纤维化的分子机制提供新的见解。相关性(见说明)：肺纤维化是一种毁灭性的疾病，目前还没有有效的治疗或治愈方法。我们假设，规范的Wnt信号是纤维化的原因介质，并通过直接激活影响成纤维细胞增殖/激活的基因来促进纤维化。这项提案的发现将为这种疾病的分子机制提供新的见解，并转化为开发迫切需要的肺纤维化疗法。(摘要结束)

DESCRIPTION (provided by applicant): This proposal describes a career development plan to become a successful independent investigator and to elucidate novel molecular mechanisms in the development of pulmonary fibrosis. For this proposal, the principal investigator has brought together the expertise and experience from two leading scientists, Dr. John Varga and Dr. Cara Gottardi, in the respective fields of fibrosis and Wnt signaling to create a unique environment for exceptional mentorship in studying pulmonary fibrosis. Additional scientific and career advice will be provided by an advisory committee comprised of highly-regarded physician-scientists from the Division of Pulmonary and Critical Care Medicine at Northwestern University. Through a variety of didactic and research training modalities, this proposal will develop expertise in cell and molecular biology of the lung, especially with regard to pulmonary fibrosis. The research will be the first to demonstrate a direct causal role of beta-catenin signaling in pulmonary fibrosis and will dissect the effects of canonical Wnt/beta- catenin signaling in lung fibroblasts. In this proposal, human lung fibroblast cells will be used for in vitro studies, while transgenic gain- and loss-of-function murine bleomycin models will be used to recapitulate human pulmonary fibrosis in vivo. The aims of this proposal are: 1) To determine whether increased beta- catenin activity resulting from loss of the negative regulator, Axin2, worsens fibrosis in a bleomycin-induced pulmonary fibrosis model, 2) To determine whether decreased beta-catenin activity resulting from loss of the Wnt co-receptor, Lrp5, attenuates the bleomycin-induced fibrosis phenotype, 3) To determine whether canonical Wnt signaling is required and sufficient to increase cell proliferation via cyclin D, migration via MMP7, and transdifferentiation in human lung fibroblasts. The findings of this proposal will demonstrate the first direct causal link between the canonical Wnt/beta-catenin pathway and lung fibrosis and provide novel insights into the molecular mechanism of pulmonary fibrosis. RELEVANCE (See instructions): Fibrosis of the lung is a devastating disease for which there is currently no effective treatment or cure. We hypothesize that canonical Wnt signaling is a causal mediator of fibrosis and promotes fibrosis through the direct activation of genes that affect fibroblast proliferation/activation. The findings from this proposal will provide novel insights into the molecular mechanism for this disease and translate into the development of desperately needed therapeutics for pulmonary fibrosis. (End of Abstract)