Role of Wnt/b-catenin signaling in pulmonary fibrosis

Wnt/b-连环蛋白信号在肺纤维化中的作用

• 批准号: 8318143
• 负责人: AI P LAM
• 金额: $ 12.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-02 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318143
• 关键词: Advisory Committees; Affect; Attenuated; Biopsy; Biopsy Specimen; Bleomycin; Cell Differentiation process; Cell Proliferation; Cells; Cellular biology; Clinical; Connective Tissue; Critical Care; Cyclin D1; Data; Development; Development Plans; Disease; Effector Cell; Environment; Epithelium; Fibroblasts; Fibrosis; Functional disorder; Gene Activation; Hamman-Rich syndrome; Human; In Vitro; Instruction; Light; Link; Lung; Lung Inflammation; Malignant Neoplasms; Matrilysin; Mediating; Mediator of activation protein; Medicine; Mentorship; Microarray Analysis; Modality; Modeling; Molecular; Molecular Biology; Mus; Muscle; Pathway interactions; Patients; Phenotype; Physicians; Principal Investigator; Pulmonary Fibrosis; Research; Research Personnel; Research Training; Role; Scientist; Signal Pathway; Signal Transduction; Steroids; Survival Rate; Systemic Scleroderma; Therapeutic; Tissue Sample; Tissues; Transgenic Organisms; Translating; Universities; Up-Regulation; Wound Healing; abstracting; age related; beta catenin; career; career development; effective therapy; experience; fibrogenesis; human SFRP4 protein; in vivo; inhibitor/antagonist; innovation; insight; loss of function; migration; novel; receptor; response; transdifferentiation

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)

描述（由申请人提供）：该提案描述了一个职业发展计划，成为一名成功的独立研究者，并阐明肺纤维化发展的新分子机制。对于该提案，首席研究员汇集了两位领先的科学家John Varga博士和Cara Gottardi博士在纤维化和Wnt信号各自领域的专业知识和经验，为研究肺纤维化创造了一个独特的环境。另外的科学和职业建议将由西北大学肺病和危重病医学部备受尊敬的内科科学家组成的咨询委员会提供。通过各种教学和研究培训方式，该建议将发展肺细胞和分子生物学方面的专业知识，特别是关于肺纤维化。该研究将首次证明β -catenin信号在肺纤维化中的直接因果作用，并将剖析典型Wnt/ β -catenin信号在肺成纤维细胞中的作用。在这个提议中，人肺成纤维细胞将用于体外研究，而转基因的功能获得和功能丧失的小鼠博来霉素模型将用于概括体内的人肺纤维化。本建议的目的是：1)为了确定β -连环蛋白活性的增加是否由于负调节因子Axin2的缺失而加重了博来霉素诱导的肺纤维化模型中的纤维化，2)为了确定β -连环蛋白活性的降低是否由于Wnt共受体Lrp5的缺失而减弱了博来霉素诱导的纤维化表型，3)为了确定典型的Wnt信号是否需要并足以通过cyclin D增加细胞增殖，通过MMP7迁移，以及人肺成纤维细胞的转分化。该研究结果将首次证明典型Wnt/ β -连环蛋白通路与肺纤维化之间的直接因果关系，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疾病，目前尚无有效的治疗或治愈方法。我们假设典型Wnt信号是纤维化的因果介质，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。这一发现将为该病的分子机制提供新的见解，并转化为肺纤维化迫切需要的治疗方法的发展。（摘要结束）