个人简介
Born to be a (multi)cellular physiologist in Budapest, Hungary, I got my MD at the Semmelweis University in 1986. I got mesmerized by research as a second year medical student at Department of Physiology, and here I remained after graduation to obtain my PhD in 1992 under the guidance of Drs. A Fonyo and G.L Lukacs from the (patho)physiology of mitochondrial cation transport. My main achievements is this period included the characterization of the mitochondrial Na+/H+ exchanger (NHE) and the Ca2+ uniporter, the first continuous measurement of of intramitochondrial pH and Ca2+, and the identification of the physiologic role of the latter (with G.L Lukacs) as a key regulator of the citric acid cycle. I continued with the functional characterization of a novel H+ channel in phagocytes, a topic that drove to perform a postdoc (1992-95) under the supervision of Dr. S Grinstein at Divison of Cell Biology at the Hospital for Sick Children, Toronto. I performed the patch clamp analysis of the new H+ channel and identified the functional differences of plasma membrane NHE isoforms. Here I also got infected with my lifelong interest – the question of how biophysical parameters such as cell volume, tension/contractility and surface charge are converted to biochemical signals and influence cell fate and plasticity. Particularly I sought to understand how cytoskeleton organization regulates transport and gene transcription. I moved to Canada in 1997 and became a PI at the Toronto General Research Institute (1997-2003) and the St. Michaels’s Hospital/Keenan Research Centre (KRC) (2003-present), and was appointed at the Department of Surgery (1999) and Biochemistry (2013). We investigated the organization and role of the cytoskeleton in the context of osmostress and of epithelial mesenchymmal transition (EMT), a key process in organ fibrosis and cancer. Currently we aim at understanding how the cytoskeleton regulates nucleocytopalmic traffic of transcription factors and thus phenotype, plasticity, particularly during organ fibrosis and myofibroblats generation. Our main results include the description of cell volume-dependent regulation of Rho GTPases and a novel kinase cascade, the identification the regulatory role of cell contacts in EMT, the description of the two-hit model (contact-injury and the fibrogenic cytokine TGFβ) of EMT/epithelial-myofibroblast transition, the concept of site specific susceptibility to TGFβ and of acquired ciliopathy during fibrogenesis. I have published 127 peer-reviewed papers (>7500 citations), am the head of the research training centre and the Critical Care/Inflammation Platform at KRC and the associate vice-chair of research at the Dept Surgery.
研究领域
The major interests of my lab is to understand the cellular and molecular mechanisms underlying cellular plasticity, particularly as it pertains to epithelial-mesenchymal transition (EMT) and myofibroblast formation. These processes play critical roles in wound repair and regeneration and are central to the pathobiology of organ fibrosis, i.e. injury-induced progressive and often fatal scarring of the lung, liver and kidney. Cellular plasticity i.e. the transformation of one cellular phenotype into another is governed by chemical stimuli such as growth factors (e.g. TGFβ) and cytokines, as well as by mechanical inputs such as cell contractility, forces acting on the intercellular contacts or the nucleus and tissue stiffness. We aim at understanding the interplay and the synergy between chemical and mechanical signal transduction in determining cell fate. The cytoskeleton plays a central role in the integration of various fibrogenic inputs. Accordingly, we study how the cytoskeleton is remodeled upon exposure to chemical and mechanical stress conditions (e.g. osmotic stress), and conversely how cytoskeleton remodeling controls major cell functions including gene expression, ion transport, motility and the dynamics of cellular organelles such as mitochondria, nuclei and the primary cilium. One of the central problems in this area is to uncover the mechanisms whereby cytoskeleton remodeling regulates the nucleocytoplasmic traffic of transcription factors (e.g. the Rho GTPase target myocardin-related transcription factor (MRTF) or the Hippo pathway effectors TAZ and YAP), which in turn reprogram gene expression as have fate-determining effects on phenotype. Overall our research addresses the fundamental biology and cellular pathology of injury and repair.
The biology of epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transition
Our goal is to understand how normal epithelial cells (particularly of the kidney) transform into matrix-producing (scar-forming) invasive and contractile myofibroblasts. We explore the cellular and molecular mechanisms whereby injury of the intercellular contacts leads to EMT and synergizes with fate-determining pathways such as TGFbeta signaling and the Hippo signal transduction machinery. This research allows insight into fundamental mechanisms responsible for the pathogenesis of major disease entities such as kidney and lung fibrosis and liver cirrhosis and malignant transformation.
The role of the cytoskelton in the regulation oxidatve stress
Actin polymerization impacts the generation of reactive oxygen species (ROS), but the underlying mechanisms are poorly understood. This research line aims at exploring how changes in actin dynamics, by initiating transcriptional responses or structural remodeling, alter the expression and function of ROS-generating systems.
The impact of cytsokelkton organization on organellar remodeling: effects on the primary cilium and mitochoindria
EMT, predominantly through acto-myosin-dependent processes, is associated with dramatic changes in the primary cilium, the key mechano-chemical antenna of the cell. The project aims at characterizing these effects, the underlying molecular mechanisms and the ensuing functional consequences.
Mechanical (osmotic) stress indues major structural changes (fragmentation) in mitochondria. We investigate the role of the cytoskeleton in these changes, the underlying molecular mechanisms and the ensuing functional consequences.
The role of the cytoskeleton in the regulation of the nucleocytoplasmic traffic of transcription factors
Mechanosensitive transcription factors such as MRTF and TAZ undergo nucleocytoplamsic shuttling in an actin skeleton-regulated manner. The projects aims at identifying various mechanisms whereby the cytoskeleton and cell contractility alter transcription factor shuttling (cytosolic retention, nuclear uptake, efflux, capture). These processes play a central role in mechanotransduction, the regulation of cell plasticity, fibrogenesis and proliferation.
近期论文
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Cell shrinkage regulates Src kinases and induces tyrosine phosphorylation of cortactin, independent of the osmotic regulation of Na+/H+ exchangers.
Kapus A, Szászi K, Sun J, Rizoli S, Rotstein OD
J Biol Chem. 1999 Mar 19;274(12):8093-102 Read
Osmotic stress-induced remodeling of the cortical cytoskeleton
Di Ciano C, Nie Z, Szászi K, Lewis A, Uruno T, Zhan X, Rotstein OD, Mak A, Kapus A
Am J Physiol Cell Physiol. 2002 Sep;283(3):C850-65. Read
Central role for Rho in TGF-beta1-induced alpha-smooth muscle actin expression during epithelial-mesenchymal transition
Masszi A, Di Ciano C, Sirokmány G, Arthur WT, Rotstein OD, Wang J, McCulloch CA, Rosivall L, Mucsi I, Kapus A.
Am J Physiol Renal Physiol. 2003 May;284(5):F911-24. Read
Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin
Masszi A, Fan L, Rosivall L, McCulloch CA, Rotstein OD, Mucsi I, Kapus A
Am J Pathol. 2004 Dec;165(6):1955-67 Read
Receptor activation alters inner surface potential during phagocytosis
Yeung T, Terebiznik M, Yu L, Silvius J, Abidi WM, Philips M, Levine T, Kapus A, Grinstein S.
Science. 2006 Jul 21;313(5785):347-51 Read
Cell contact-dependent regulation of epithelial-myofibroblast transition via the rho-rho kinase-phospho-myosin pathway
Fan L, Sebe A, Péterfi Z, Masszi A, Thirone AC, Rotstein OD, Nakano H, McCulloch CA, Szászi K, Mucsi I, Kapus A
Mol Biol Cell. 2007 Mar;18(3):1083-97 Read
Membrane phosphatidylserine regulates surface charge and protein localization
Yeung T, Gilbert GE, Shi J, Silvius J, Kapus A, Grinstein S
Science. 2008 Jan 11;319(5860):210-3 Read
Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for Smad3
Masszi A, Speight P, Charbonney E, Lodyga M, Nakano H, Szászi K, Kapus A
J Cell Biol. 2010 Feb 8;188(3):383-99 Read
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