Research and Clinical Focus
(1) The molecular and cell biology of the extracellular matrix, with emphasis on liver fibrosis. Exploration of the cellular, molecular and signaling mechanisms of excess ECM deposition during the development of fibrosis and cirrhosis, as well as mechanisms of its dissolution (fibrolysis). These studies are linked to translational projects that are aimed at 1. developing non-invasive techniques for monitoring fibrogenesis and fibrolysis in patients, and 2. devising and validating several potential antifibrotic and fibrosis reversal-inducing therapies. Here, experimental strategies exploit various human and experimental in vitro and vivo models of liver fibrosis, inflammation, and oxidative stress, such as primary and secondary biliary fibrosis, lobular fibrosis and non-alcoholic steatohepatitis. In parallel we develop mouse models for cystic fibrosis liver disease and primary liver cancer. In vitro studies are performed with activated hepatic stellate cells, myofibroblasts, Kupffer cells, lymphocytes and NKT cells, partly in conjunction with the Koziel and Exley labs at BIDMC and DFCI. By using proteomics and techniques of molecular targeting/imaging in cooperation with the Libermann and Frangioni labs at BIDMC/DFCI, respectively, major efforts are being invested in the development of diagnostic methods that will allow noninvasive quantification of fibrogenesis and fibrolysis, a necessary prerequisite for the validation of antifibrotic therapies in patients. Other projects explore bone marrow stem cell therapy for therapy of cirrhosis (with Yale), bioengineering/nanotechnology for the liver (with the Bhatia lab at MIT), lymphocyte-derived microparticles as fibrolytic agents, and the role of micro-RNA in the regulation of liver fibrogenesis. These activities are embedded within and tightly linked to the clinical activities of the
Liver Center at BIDMC.
(2) The molecular pathogenesis and immunology of chronic intestinal diseases, in particular of celiac disease. Prior and current research has lead to the identification of the celiac disease autoantigen, tissue transglutaminase, and focused on exploring the role of tTG in celiac disease pathogenesis. Several approaches have been undertaken to develop a mouse model for celiac disease, in order to allow the preclinical testing of non-dietary therapies. We could already create a celiac mouse model by transfer of gluten sensitized T cell subsets to immunodeficient recipients subsequently exposed to a gluten containing diet. The model is currently used for mechanistic studies regarding gut homing of lymphocytes and oral tolerance induction (collaboration with the Terhorst lab at BIDMC, and the Mora lab at MGH). Other approaches, using mice that are transgenic for major human genes that predispose to celiac disease, are in process. Moreover, we aim to identify the intestinal epithelial gluten receptor that mediates transcellular transport of these peptides into the lamina propria where the destructive immune response occurs. Finally, we identify innate immune receptors for certain gliadin peptides that induce proinflammatory signals which drive the adaptive immune response to gluten, and aim to establish and validate novel serum assays that will permit to detect early and minimal gluten exposure. These activities are embedded within and tightly linked to the clinical activities of the
Celiac Center at BIDMC.