Michele Pritchard, PhD

Assistant Professor
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


Research Interests:

Alcohol-induced liver injury, inflammation and innate immunity, transcriptional control of inflammatory gene expression, wound-healing response, hepatic fibrosis, hepatic stellate cell biology, congenital hepatic fibrosis/ARPKD

Prolonged alcohol abuse promotes a step-wise progression of increasingly more severe liver injury; this progression begins with lipid accumulation (steatosis) in hepatocytes.  Twenty percent of steatotic patients will progress to hepatitis and of those, 50% will further progress to fibrosis, cirrhosis and, in some cases, hepatocellular carcinoma.  Despite the many advances in our understanding of the mechanisms which promote fibrosis, efficacious therapies remain elusive.  Indeed, the only cure for advanced stages of liver disease, regardless of etiology, is liver transplantation.  Due to the burgeoning population of patients requiring liver transplantation in the Western population, organ availability is becoming increasingly limited.  Therefore, there is an urgent need to identity novel approaches to halt the progression of alcoholic liver disease and facilitate hepatic healing to reduce the requirement for organ transplantation.     

We have focused our efforts on hepatic fibrosis as it is the last reversible stage of liver disease.  Once patients progress to cirrhosis, the liver can no longer repair itself sufficiently to reinstate normal liver function.  The overall goal of our research program is to discover new mechanisms which contribute to hepatic fibrogenesis from which we can design novel therapeutic strategies.

Liver fibrosis and ethanol: Role of the transcription factor, Egr-1

Early growth response (Egr)-1 is a redox-sensitive transcription factor that regulates a broad array of genes involved in the inflammatory, anti-oxidant and wound-healing responses.  Egr-1 is a positive regulator of ethanol-induced fatty liver injury and acute hepatic inflammation in mice.  Indeed, mice that are deficient in Egr-1 have reduced liver injury in these models associated with reduced hepatic inflammatory signatures.  Paradoxically, in a mouse model of carbon tetrachloride-induced liver injury and fibrosis, Egr-1 is protective.  Collectively, these data illustrate the importance of differential gene regulation in the hepatic injury vs wound healing responses.

The reactive byproducts of ethanol metabolism cause oxidative injury to the liver.  In animal models, this injury does not cause fibrosis therefore, most liver fibrosis researchers rely on the use of fibrogenic hepatotoxicants to model human alcoholic liver disease.  To more closely recapitulate human disease, we use a mouse model in which we combine moderate ethanol feeding to mice with carbon tetrachloride exposure.  Moderate ethanol feeding to mice exacerbates carbon tetrachloride-induced profibrotic changes in the liver in wild-type mice in the absence of increased liver injury.  Interestingly, this effect is worsened if the mice are deficient in Egr-1 and is associated with reduced expression of anti-oxidant genes in liver.  Hepatic stellate cells (HSC) are mainly responsible for fibrotic changes in the liver. Consistent with our in vivo data, HSC isolated from Egr-1-deficient mice exhibit an increased fibrotic phenotype after activation on tissue culture plastic when compared to HSC isolated from wild-type mice.

Using a combination of genetic and therapeutic approaches, we are testing the hypothesis that ethanol feeding to mice exacerbates carbon tetrachloride-induced hepatic fibrogenesis through reduced, Egr-1-dependent, antioxidant defenses.

Hyaluronan and hepatic fibrosis

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 differential 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 and lung, little is known about the role of HA in liver fibrosis.

In our current studies, we are investigating the roles of HA in hepatic inflammation and fibrosis.  We hypothesize that HA modulates the hepatic microenvironment during liver injury and repair processes.  To begin to test this hypothesis, we are characterizing carbon tetrachloride-induced fibrosis mice deficient in enzymes responsible for HA biosynthesis. Our preliminary data suggest that deficiency of certain hyaluronan synthase (Has) isoforms enhances carbon tetrachloride-induced profibrotic changes in the liver.  Consistently, the fibrotic phenotype of primary hepatic stellate cells activated on tissue culture plastic is also greater in cells isolated from certain Has-deficient mice compared to controls.

Congenital hepatic fibrosis in autosomal recessive polycystic kidney disease

Congenital hepatic fibrosis (CHF), the most common extra-hepatic manifestation of 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 perinatal lethality develop severe portal hypertension associated with the CHF around the progressively developing hepatic cysts. The precise mechanisms of hepatic cystogenesis and associated CHF are not known. In addition, therapeutic options for ARPKD/CHF are extremely limited and rely on combined kidney and liver transplant for patient survival.  Very recently, in collaboration with Udayan Apte, PhD, DABT also in the Department of Pharmacology, we have begun to elucidate the molecular mechanisms responsible for CHF in ARPKD. In these studies, we are using a rat model, the polycystic kidney (PCK) rat, which harbors a mutation in the Pck gene, orthologous to the PKHD1 gene responsible for human ARPKD. Mutation of Pck in the PCK rat recapitulates the human disease phenotype, making this a valuable model for our research.  We are comparing these animal model data to human patient samples to validate the relevance our findings to the human disease.

In summary, it is the goal of these three projects to elucidate novel mechanisms which contribute to hepatic fibrosis and use those discoveries to design new therapeutic approaches to halt the progression and accelerate reversal of hepatic fibrosis. 

Selected Publications:

(* indicates manuscripts for which I am corresponding author.)

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. 37(10):1668-79, 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 g-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.

Last modified: Dec 20, 2013

mpritchard

Contact

Michele Pritchard, PhD
Assistant Professor

4091 HLSIC; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160

P: (913) 588-0383
F: (913) 588-7501
mpritchard@kumc.edu

COBRE Project

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