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.
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.
|Reinke, Lauren; Lam, Anna P; Flozak, Annette S et al. (2016) Adiponectin inhibits Wnt co-receptor, Lrp6, phosphorylation and Î²-catenin signaling. Biochem Biophys Res Commun 470:606-12|
|Flozak, Annette S; Lam, Anna P; Gottardi, Cara J (2016) A Simple Method to Assess Abundance of the Î²-Catenin Signaling Pool in Cells. Methods Mol Biol 1481:49-60|
|Sennello, Joseph A; Misharin, Alexander V; Flozak, Annette S et al. (2016) Lrp5/Î²-catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis. Am J Respir Cell Mol Biol :|
|dos Santos, Gimena; Rogel, Micah R; Baker, Margaret A et al. (2015) Vimentin regulates activation of the NLRP3 inflammasome. Nat Commun 6:6574|
|Lam, Anna P; Herazo-Maya, Jose D; Sennello, Joseph A et al. (2014) Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 190:185-95|
|Lam, Anna P; Gottardi, Cara J (2013) Fat in fibrosis. Am J Respir Crit Care Med 188:1268-9|
|Wei, Jun; Fang, Feng; Lam, Anna P et al. (2012) Wnt/Î²-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum 64:2734-45|
|Mutlu, GÃ¶khan M; Budinger, G R Scott; Wu, Minghua et al. (2012) Proteasomal inhibition after injury prevents fibrosis by modulating TGF-Î²(1) signalling. Thorax 67:139-46|
|Lam, Anna P; Flozak, Annette S; Russell, Susan et al. (2011) Nuclear Î²-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am J Respir Cell Mol Biol 45:915-22|
|Lam, Anna P; Gottardi, Cara J (2011) Î²-catenin signaling: a novel mediator of fibrosis and potential therapeutic target. Curr Opin Rheumatol 23:562-7|
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