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 Focus

Liver disease, hyaluronan, inflammation, wound-healing response, fibrosis, hepatic stellate cells, congenital hepatic fibrosis/ARPKD, alcohol, ovary, kidney

Our group is interested in wound healing and fibrosis after tissue injury or in response to aging. We have three projects in the lab which focus on elucidating novel mechanisms of fibrosis and fibrosis resolution.  In project #1, we explore the role of hyaluronan and the hyaluronan network in response to acute or chronic hepatotoxin-mediated liver injury. In project #2, we explore mechanisms of fibrosis in liver and kidney found in a relatively rare genetic disease (autosomal recessive polycystic kidney disease, ARPKD). In project #3, we explore mechanisms involved in organ aging and premature 'aging' after an iatrogenic insults. Brief descriptions of these three 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, fibrosis and fibrosis resolution in response to injury induced by various hepatotoxicants, including alcohol.  We hypothesize that HA can modulate the hepatic microenvironment during liver injury and repair 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 recently published data suggest that deficiency of hyaluronan synthase 3 (HAS3) enhances acute carbon tetrachloride-induced inflammation and profibrogenic changes in the liver, but not frank fibrosis after chronic carbon tetrachloride exposure. Matrix metalloprotienase 13 is responsible for enhanced matrix degradation in HAS3-deficient mice and we now have preliminary data to suggest that RHAMM (receptor for HA-mediated motility) is critical in this process. We hypothesize that HA can modulate the hepatic microenvironment during liver injury and repair.  Pritchard Supporting Image Figure 1
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.

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 accumulation which encapsulates cholangiocyte-derived cysts in the liver and renal tubule-derived cysts in the kidney. CHF is generally detected in the 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, renal 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 this gene in the PCK rat recapitulates the human disease, making it a valuable tool for our research. Using this model, we, in collaboration with Dr. Udayan Apte, are investigating the role of hepatic mast cells and the role of the Hippo kinase pathway in CHF/ARPKD. 

3.  Development of a pathological extracellular matrix in organ aging and after radiation therapy

In the past year, we have broadened our interest in wound healing and fibrosis to include two new 'pathologies': in aging and after iatrogenic insults.  This new interest was fostered by the development of a collaboration with Dr. Francesca E. Duncan (Northwestern University), a reproductive biologist interested in understanding the mechanisms behind the decline in fertility with advanced maternal age.  In June of 2016, our first collaborative study was published.  This study demonstrated, for the first time, development and progression of ovarian fibrosis and robust inflammation in mice by 22 months of age.  The findings of this study suggest that alterations in the ovarian stroma may contribute to loss of fertility associated with advanced maternal age.  Current work is exploring how the ovarian stroma changes from homeostatic to reactive driving this change.  In addition to the work on the ovary, we are exploring the mechanisms behind age-related fibrotic changes in the liver and in the liver after radiation exposure.

 

Selected Publications:

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

L. Jiang, P. Fang, J.L. Weemhoff, U. Apte, *M.T. Pritchard.  Evidence for a 'pathogenic triumvirate in congenital hepatic fibrosis (CHF) in autosomal recessive polycystic kidney disease (ARPKD). Biomed Research International, in revision.

S. Briley, S. Jasti, J.M. McCracken, J. Hornick, B. Fegley, M.T. Pritchard and F.E. Duncan. Reproductive age-associated fibrosis in the stroma of the mammalian ovary.  Reproduction. 2016. 152(3):245-60. PMCID: PMC4979755

J.M. McCracken, L. Jiang, K.T. Deshpande, M.F. O'Neil and *M.T. Pritchard. Differential effects of hyaluronan synthase 3 deficiency after acute vs chronic liver injury in mice. Fibrogenesis & Tissue Repair. 2016 9:4. PMCID: PMC4818527

K.T. Deshpande, S. Liu, J.M. McCracken, L. Jiang, T.E. Gaw, L.N. Kaydo , Z.C. Richard, M.F. O'Neil and *M.T. Pritchard. Moderate (2%, v/v) ethanol feeding alters hepatic wound healing after acute carbon tetrachloride exposure in mice.  Biomolecules. 2016. 6(1):5. PMCID: PMC4808799

*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, 2015, 16:1332 - 1346. PMCID: PMC4838187

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. Elsevier, Inc., 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. 2013. 37(10):1668-79. PMCID: PMC3796136

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, 2013. 8(7):e69114.

L.J. Dixon, M.A. Barnes, H. Tang, M.T. Pritchard and L.E. Nagy. Kupffer cells in the liver.   Compr Physiol, 2013.3:785-797.

* 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., 2011. 300(6):G1124-31.

*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. 2010. 53(4):655-662.

*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, 2010. 176(6): 2743 - 2752.

S. Roychowdhury, M.R. McMullen, M.T. Pritchard, W. Lei, R.G. Solomon and L.E. Nagy. Formation of γ-ketoaldehyde-protein adducts during ethanol-induced liver injury in mice. Free Rad. Biol. Med. 2009. 47:1526-1538.  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, 2009. 49:1326-1334. 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. 2008. 632:175-186.

* 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. 2007. 293:G1124-G1133.

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, 2007. 132(3):1117-1126.  PMCID: PMC1838572

M.T. Pritchard and L. E. Nagy.  Ethanol-induced liver injury:  potential roles for Egr-1.  Invited review.  Alcohol. Clin. Exp. Res. 2005. 29:146S-150S.

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, 2005. 128:2066-2076.

Last modified: Aug 31, 2016

Michele Pritchard, Ph.D.

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

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