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Division of Pulmonary and Critical Care Medicine
David Lagares, PhDDirector of the Matrix and Mechanobiology Program, Fibrosis Research Center, Massachusetts General Hospital Principal Investigator, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital
Lagares Laboratory: Tissue Repair, Regeneration and Fibrosis
The ability of organs to regenerate following injury declines with age. In older aged individuals, chronic tissue injury leads to abnormal wound healing responses characterized by the development of scar tissue or fibrosis and subsequent organ failure. The identification of novel therapeutic strategies aiming at reducing tissue fibrosis and promoting the regeneration of damaged tissues is a major unmet clinical need in regenerative medicine.
The goal of the Lagares Laboratory is to understand the cellular and molecular mechanisms that regulate the delicate balance between organ regeneration and fibrosis following tissue injury, with an emphasis on the biochemical and biomechanical drivers of scar-forming myofibroblast activation. Ultimately, we seek to develop novel anti-fibrotic therapies for the treatment of human diseases such as idiopathic pulmonary fibrosis, systemic sclerosis, liver cirrhosis, progressive kidney disease and desmoplastic tumors.
The Lagares Laboratory at Massachusetts General Hospital utilizes cutting-edge molecular biology techniques, new bioengineering assays, genetic manipulation of mice, animal modeling of tissue injury and fibrosis and translational studies in humans to understand the biology of fibrotic diseases and ultimately develop innovative anti-fibrotic therapies.
The ADAM10-sEphrin-B2 pathway in lung injury and fibrosis
The identification of the molecular mediators directing activation of scar-forming myofibroblasts in organ fibrosis may provide novel targets for anti-fibrotic therapy. We have recently identified soluble ephrin-B2 (sEphrin-B2) as a new profibrotic mediator in lung fibrosis. Using mouse models of lung injury and fibrosis, we have demonstrated that the ectodomain of membrane-bound ephrin-B2 is shed by ADAM10 into the alveolar airspace following lung injury. Once shed, sEphrin-B2 is sufficient to drive myofibroblast formation and fibrosis. In genetic studies, we have demonstrated that mice lacking ephrin-B2 in fibroblasts exhibit marked protection from lung fibrosis. In humans, ADAM10/sEphrin-B2 signaling is upregulated in fibroblasts from patients with idiopathic pulmonary fibrosis, a fatal age-related fibrotic lung disease. Our studies identify sEphrin-B2, its receptors EphB3 and EphB4 and ADAM10 as novel therapeutic targets in lung fibrotic diseases.
Mechanobiology of fibrotic diseases
Tissue stiffening has traditionally thought to simply be a consequence of fibrosis. We have recently shown that matrix stiffness is a major contributing factor to fibrosis progression through mechano-activation of myofibroblasts. Our results suggest that there is a feed-forward loop between matrix stiffening and fibroblast activation that amplifies fibrosis progression, but the mechanisms of this amplification loop have yet to be determined. Understanding the cellular and molecular determinants of progressive matrix stiffening consequently may help to improve understanding of the pathogenesis of fibrotic diseases and identify new therapeutic targets for it. We have demonstrated in a series of publications that targeting mechanotransduction pathways in activated myofibrobalsts dramatically ameliorated organ fibrosis in mouse models. Our research projects focus on the role of mechanotransduction pathways including integrin signaling, FAK, ROCK, YAP/TAZ and MRTF-A in regulating fibroblast activation in tissue injury and fibrosis.
Targeted apoptosis of myofibroblasts in fibrosis
Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis. We have recently demonstrated that mechano-activation of myofibroblasts increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells, which become “primed for death” by pro-apoptotic signals such as the BH3-only protein BIM. Primed myofibroblasts are “addicted” to anti-apoptotic protein BCL-XL to sequester BIM and ensure myofibroblast survival. In preclinical studies, we have demonstrated that selective pharmacological inhibition of BCL-XL with the BH3 mimetic ABT-263 (navitoclax) reverses established skin fibrosis by inducing myofibroblast apoptosis. In humans, dermal fibroblasts derived from patients with scleroderma (an autoimmune fibrotic disease) are similarly primed for death and more sensitive to ABT-263-induced apoptosis than control fibroblasts. Our findings explain the potential efficacy of targeting myofibroblast anti-apoptotic proteins with BH3 mimetic drugs in scleroderma and other fibrotic diseases.
If you are interested in applying for a postdoctoral position, or are a Harvard PhD student interested in a laboratory rotation, please e-mail your CV and a list of reference to Dr. David Lagares (email@example.com).
Full list of publications from David Lagares, PhD.
The Lagares Laboratory
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