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Principal Investigator, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital
Associate Physician, Pulmonary and Critical Unit, Massachusetts General Hospital
Associate Professor of Medicine, Harvard Medical School
Investigations of lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) in the pathogenesis of pulmonary fibrosis in idiopathic pulmonary fibrosis and the acute respiratory distress syndrome, and of dermal fibrosis in scleroderma.
Fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and scleroderma are associated with high morbidity and mortality, with outcomes largely unaffected by current therapies. Improved understanding of the biologic processes involved in development of fibrosis in these diseases, and more complete identification of the molecular mediators driving these processes, are urgently needed to develop effective new therapies. We have recently found that the potent lipid mediators lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) direct multiple processes fundamentally involved in fibrogenic responses to injury, including epithelial cell apoptosis, vascular leak, and fibroblast recruitment and persistence.
We have found that LPA signaling through one of its receptors, LPA1, is critically required for the development of pulmonary and dermal fibrosis in mice following bleomycin-induced injury of these tissues: LPA1-deficient mice are dramatically protected from fibrosis in these commonly used models of IPF and scleroderma. We have also found that LPA levels are increased in the BAL fluid of patients with established IPF, that LPA1 is highly expressed by fibroblasts recovered from IPF BAL, and that pharmacological antagonism of LPA1 markedly reduces fibroblast responses ex vivo to the chemotactic activity of IPF BAL. In our studies of S1P in fibrotic disease, we have recently demonstrated that inhibition of S1P-S1P1 signaling dramatically worsened vascular leak induced by bleomycin lung injury. In these studies, we found that mice developing increased leak from S1P1 antagonism also went on to develop markedly increased lung fibrosis following bleomycin injury. We are now pursuing multiple studies described in the Research Projects section of this site, to further define the roles of these important mediators, and potential targets for novel therapies, in both mouse models and translational studies of fibrotic diseases.
Investigations of HIV pathogenesis in a humanized mouse model of HIV infection. The development of a safe and effective HIV vaccine is a global health priority, but will require improved understanding of the immunopathogenesis of HIV infection. An ideal animal model in which to study the pathogenesis of HIV infection has been elusive, however. There has been increased interest in humanized mouse models of HIV infection, although the absence of robust anti-HIV human immune responses in these models to date has suggested that they are not yet ready to test immune responses to vaccine candidates. Recently, we and others have developed an improved humanized mouse model of HIV by transplanting human CD34+ stem cells and autologous human thymic grafts into immunodeficient mice. In this model, we have achieved robust repopulation of mouse lymphoid tissues with human immune cells, and have generated robust anti-HIV cellular and humoral immune responses in these humanized mice. We believe this improved humanized mouse model will allow us to study questions regarding the biology of HIV not readily approachable through human studies. Currently, we are using our humanized mouse model of HIV infection to investigate the immunogenecity and protective efficacy of several candidate HIV vaccines, as well as the mechanisms of viral dissemination, of HIV-induced immune activation, and of HIV-induced immune dysfunction. Specific studies are described in the Research Projects section of this site. In addition to our own investigations, we have recently initiated a humanized mouse program for the Harvard University Center for AIDS Research (HU CFAR) and the Ragon Institute of MGH, MIT and Harvard, through which we are making humanized mice available to HU CFAR and Ragon collaborators.
Investigations of HIV pathogenesis in a humanized mouse model of HIV infection.
Collaborations with investigators from Harvard University Center for AIDS Research (HU CFAR) and the Ragon Institute of MGH, MIT and Harvard.
Please contact Dr. Tager via e-mail.
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