Ph.D. State University of New York at Buffalo, Roswell Park Graduate Division, 2003
Postdoctoral Fellow, Case Western Reserve University, 2006
Postdoctoral Fellow, Cleveland Clinic, 2008
Research Associate, Cleveland Clinic, 2009
Project Scientist, Cleveland Clinic, 2011
Assistant Professor, Case Western Reserve University, 2012
Liver disease, inflammation, wound-healing response, hepatic fibrosis, hepatic stellate cell biology, congenital hepatic fibrosis/ARPKD, alcohol
Our group is interested in liver fibrosis. We have two projects in the lab which focus on elucidating novel mechanisms of fibrosis and fibrosis resolution. In one project, we explore these mechanisms as they pertain to hepatotoxin-mediated liver fibrosis. In the other project, we are interested in mechanisms of fibrosis found in a relatively rare congenital liver disease. Brief descriptions of these two projects are found below.
1. Hyaluronan and the hepatic wound healing response after acute and chronic liver injury
Hyaluronan (HA), an extracellular matrix glycosaminoglycan, is increased in the plasma of patients with liver disease; HA plasma concentration directly correlates with liver disease severity. HA has different biological functions based on molecular mass; low molecular mass HA promotes inflammation and angiogenesis while high molecular mass HA promotes tissue homeostasis. While much research is devoted to understanding the roles of HA in inflammation and fibrosis in the skin, lung and intestine, little is known about the role of HA in the liver. We are currently investigating the roles of HA in hepatic inflammation and fibrosis. We hypothesize that HA can modulate the hepatic microenvironment during liver injury and repair
Figure 1. Therapeutic targets for liver fibrosis. Several intervention points exist for which therapeutic strategies for liver fibrosis can be or are being developed. Some of the factors which contribute to liver fibrosis are written in black and found outside the circle. Some therapeutic strategies/targets are written in red and found inside the circle. Published evidence suggests that the extracellular matrix glycosaminoglycan, hyaluronan (HA), in its native, high molecular weight form, has the potential to reduce chronic inflammation, facilitate tissue repair and improve the extracellular matrix compliance. Leveraging HA's anti-inflammatory and pro-homeostatic functions may 'fetalize' the liver response to chronic injury and therefore improve hepatic wound healing and attenuate fibrosis or facilitate fibrosis resolution.
processes; how it modulates these parameters depends on HA molecular mass. Indeed, fetal wounds, wounds which contain elevated levels of high molecular mass HA, heal without a scar. Therefore, we believe that 'fetalizing' hepatic wound healing through modulation of HA content and size will reduce fibrosis. To test this hypothesis, we are making use of various genetic and pharmacologic approaches in mouse models. Our preliminary data suggest that deficiency of certain hyaluronan synthase (HAS) isoforms enhances acute carbon tetrachloride-induced inflammation and profibrogenic changes in the liver, but not frank fibrosis after chronic carbon tetrachloride exposure. Recently, we identified matrix metalloprotienase 13 as a critical mediator of enhanced resolution of hepatic fibrosis in HAS enzyme deficient mice and have preliminary data to suggest that RHAMM (receptor for HA-mediated motility) is critical in this process.
2. Congenital hepatic fibrosis in autosomal recessive polycystic kidney disease
Congenital hepatic fibrosis (CHF), the most common extra-renal manifestation of autosomal recessive polycystic kidney disease (ARPKD), is associated with excessive extracellular matrix deposition which encapsulates ductal plate cell-derived cysts. CHF is generally detected in perinatal period and is often fatal. Infants who survive the perinatal period develop severe portal hypertension associated with the CHF around the progressively developing hepatic cysts. The precise mechanisms of hepatic cystogenesis and associated CHF are unknown. In addition, therapeutic options for CHF/ARPKD are extremely limited and rely on combined kidney and liver transplant for patient survival. We use the polycystic kidney (PCK) rat model which harbors a mutation in a gene orthologous to the human PKHD1 gene for our studies. Mutation in the pck gene in the PCK rat recapitulates the human disease, making this a valuable tool for our research. Using this model, we are investigating the role of hepatic mast cells and the role of the Hippo kinase pathway in CHF/ARPKD.
(* indicates manuscripts for which I am corresponding author.)
J.M. McCracken, K.T. Deshpande and *M.T. Pritchard. Hyaluronan synthase 3-deficiency exacerbates liver injury and inflammation but enhances extracellular matrix metabolism after carbon tetrachloride exposure in mice. Am J Physiol-Gastrointest Liver Dis. Submitted (Aug 2015).
*M.T. Pritchard and J.M. McCracken. Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar? Guest Editors: Lixin Zhu, Ph.D. and Susan S. Baker, MD, Ph.D. Cur Drug Targets, accepted (July 2015)
M.T. Pritchard and U. Apte. Animal models to study liver regeneration in Liver Regeneration: Basic Mechanisms, Relevant Models and Clinical Applications. Udayan M. Apte, Ph.D., DABT, Editor by Elsevier. In press (May 2015).
D.A. DeSantis, P. Lee, S.K. Doerner, C.W. Ko, J.H. Kawasoe, A.E. Hill-Baskin, S.R. Ernest, P. Bhargava, K.Y. Hur, G. Cresci, M.T. Pritchard, C.H. Lee, L.E. Nagy, J.H. Nadeau and C.M. Croniger. Genetic resistance to liver fibrosis on A/J mouse chromosome 17. Alcohol. Clin. Exp. Res. Accepted manuscript, June 2013
D.J. Chiang, S. Roychowdhury, K. Bush, M.R. McMullen, S. Pisano, M.T. Pritchard and L.E. Nagy. Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis. PLoS ONE, 8(7):e69114, 2013.
L.J. Dixon, M.A. Barnes, H. Tang, M.T. Pritchard and L.E. Nagy. Kupffer cells in the liver. Compr Physiol, 3:785-797, 2013.
* M.T. Pritchard, R.N. Malinak and L.E. Nagy: Early growth response (Egr)-1 is required for timely cell cycle entry and progression in hepatocytes after acute carbon tetrachloride exposure in mice. Am. J. Physiol.- Gastr. Liver Physiol., 300(6):G1124-31, 2011.
*M.T. Pritchard, J.I Cohen, S. Roychowdhury, B.T. Pratt and L.E. Nagy. Egr-1promotes hepatoprotection and attenuates carbon tetrachloride-induced liver injury in mice. J Hepatol. 53(4):655-662, 2010.
*M.T. Pritchard and L.E. Nagy. Hepatic fibrosis is enhanced and accompanied by robust oval cell activation in Egr-1-deficient mice after chronic carbon tetrachloride administration. Am J Pathol, 176(6): 2743 - 2752, 2010.
S. Roychowdhury, M.R. McMullen, M.T. Pritchard, W. Lei, R.G. Solomon and L.E. Nagy. Formation of -ketoaldehyde-protein adducts during ethanol-induced liver injury in mice. Free Rad. Biol. Med. 47:1526-1538, 2009. PMCID: PMC2783279
S. Roychowdhury, M.R. McMullen, M.T. Pritchard, M.E. Medof, A.B. Stavitsky and L.E. Nagy. An early complement dependent and TLR4 independent phase in the pathogenesis of ethanol-induced liver injury. Hepatology, 49:1326-1334, 2009. PMCID: PMC2666108
M.T. Pritchard, M.R. McMullen, M.E. Medof, A.B. Stavitsky and L.E. Nagy. Role of complement in ethanol-induced liver injury. Invited book chapter in Current Topics on Complement, Volume II, John D. Lambris, Ph.D. Editor. Adv in Exp Med Biol., 632:175-186, 2008.
* M.T. Pritchard, S. Roychowdhury, M.R. McMullen, L. Guo, G.E. Arteel and L.E. Nagy. Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice. Am. J. Physiol.- Gastr. Liver Biol., 293:G1124-G1133, 2007.
M.T. Pritchard, M.R. McMullen, A.B. Stavitsky, J.I. Cohen, F. Lin, M.E. Medof, L.E. Nagy. Differential contributions of C3, C5 and decay accelerating factor to ethanol-induced fatty liver in mice. Gastroenterology, 132(3):1117-1126, 2007. PMCID: PMC1838572
M.T. Pritchard and L. E. Nagy. Ethanol-induced liver injury: potential roles for Egr-1. Invited review. Alcohol. Clin. Exp. Res., 29:146S-150S, 2005.
M.R. McMullen, M.T. Pritchard, Q. Wang and L.E. Nagy. Early growth response-1 transcription factor is essential in the development of ethanol-induced fatty liver injury in mice. Gastroenterology, 128:2066-2076, 2005.