Laura W. Schrum, PhD
Research GroupDirector, Liver, Digestive and Metabolic Disorders Laboratory
Cannon Research Center
Prior Positions and Experience
||Associate Professor, Department of Biology, University of North Carolina at Charlotte (Charlotte, NC)
||Assistant Professor, Department of Biology, University of North Carolina at Charlotte (Charlotte, NC)
||Research Assistant Professor, Department of Biology, University of North Carolina at Charlotte (Charlotte, NC)
||Research Analyst, Department of General Surgery, University of North Carolina at Chapel Hill (Chapel Hill, NC)
||Postdoctoral Fellow, NIH National Research Service Award, Department of Medicine, University of North Carolina at Chapel Hill (Chapel Hill, NC)
BS (summa cum laude): 1988, North Carolina State University (Raleigh, NC)
PhD: 1993, North Carolina State University (Raleigh, NC)
Research in Liver, Digestive, and Metabolic Diseases
For the past 16 years Dr. Schrum has been dedicated to investigating the intricate cellular and molecular mechanisms of liver fibrosis. Liver fibrosis is characterized by an increase in type I collagen deposition which alters the normal liver architecture leading to liver dysfunction. Many etiologies have been associated with hepatic fibrosis with chronic alcohol consumption being the leading cause of liver fibrosis in the United States. The hepatic stellate cell (HSC) is the primary cell type in the liver responsible for excess synthesis of collagen during fibrosis. Following exposure to a fibrogenic stimulus (e.g. alcohol, toxins, viruses, etc.), the HSC transdifferentiates from a quiescent, vitamin A storing cell to an activated, collagen producing myofibroblast-like cell. HSC activation has been implicated with increased oxidative stress, thus, diminishing oxidative damage through antioxidants may serve as successful therapeutic treatments for liver diseases. S-adenosyl-L-methionine (SAMe), the precursor of glutathione, has potential usefulness as an antioxidant. SAMe has been shown to improve hepatic fibrosis; however, the molecular mechanisms of SAMe in liver fibrosis are not understood completely. Additionally, further investigation into the direct cellular/molecular effects of SAMe on the activated HSC is warranted. The role of SAMe as an antioxidant implicates the redox-sensitive transcription factor nuclear factor kappa B (NFkB) and the pathway(s) that regulates its activity as being a key player which may mediate the antioxidant effects of SAMe. NFkB and other transcription factors have been shown to modulate collagen expression in the HSC. Thus, we hypothesize that SAMe can inhibit collagen expression by modulating the activity of NFkB in the HSC. Our studies revealed that SAMe inhibits collagen expression mediated through NFkB. Furthermore, SAMe impedes proper collagen processing resulting in increased ubiquitination and decreased secretion. Overall, these findings may represent a new therapeutic target for modulation of type I collagen expression in activated HSCs.
Sex differences are observed in alcoholic liver disease with females being more susceptible to liver damage; however, it is not clear if these differences are due to developmental (perinatal) or acute exposure to sex steroidal hormones. A collaboration between CMC (Dr. Laura Schrum, Herbert Bonkovsky and Nury Steuerwald) and UNCC (Dr. Yvette Huet) has been established to investigate these sex differences. Our data indicates testosterone imprinting confers sex differences in alcoholic liver disease. Future studies will examine epigenetic regulation of alcohol metabolizing enzymes and other host defense mechanisms including oxidative stress and immune responses between males and females.
A new area of research for Dr. Schrum, in collaboration with Dr. Iain McKillop, Research Group Director, Department of Surgery, CMC, is reversal of liver fibrosis mediated by HSC apoptosis or programmed cell death. Sustained HSC activation leads to hepatic cirrhosis, a leading cause of death worldwide. Aquaporins (AQPs) are critical proteinacious channels that mediate cellular water loss during the initiation and progression of apoptosis.Our findings suggest that increased resistance to apoptosis in activated HSCs is due, at least in part, to changes in AQP expression and function. Our studies demonstrated that HSCs express AQPs and suggest that regulation of AQP expression/function contributes to HSC susceptibility to an apoptotic challenge. These data indicate it will be of considerable interest to study AQP expression and apoptosis in HSCs using animal models of progressive liver injury in which the magnitude and duration of the hepatic insult can be manipulated. In doing so, direct or indirect modulation of AQP expression in HSCs may lead to the development of novel therapeutics for the treatment of hepatic fibrosis.
Dr. Schrum's lab is also interested in understanding the molecular mechanisms leading to the transdifferentiation of the quiescent HSC to the myofibroblast-like cell which is a key event in liver fibrosis. We propose that as HSCs transdifferentiate, two separate stimuli are required for activation. An initial signal is needed to dedifferentiate HSCs from the quiescent phenotype, and a second signal is needed to differentiate the HSCs into the myofibroblastic phenotype. Ethanol and/or its metabolite acetaldehyde provide one of these signals. Understanding what signal causes these cells to undergo transdifferentiation is a clear point of intervention in cases of early, or even late hepatic fibrosis. Further, understanding the detailed genetic expression associated with the daily changes during the entire transdifferentiation process will allow a greater ability to assess the effects of various stimulants as well as provide more possible points for intervention. Our studies indicate that signaling through the JAK/STAT pathway is important for early HSC activation.
Dr. Schrum has an ongoing collaboration with Dr. Chris Yengo from Penn State investigating the role and expression profile of nonmuscle myosin II (NMM II) isoforms in quiescent and activated HSCs. Regulation of liver microcirculation is a complex system where blood flow is under systemic and sinusoidal control. Under normal conditions, quiescent HSCs wrap around sinusoids to regulate diameter, and thus blood flow, by contracting and dilating in response to local vasoconstrictors and vasodilators. However, activated HSCs exert a sustained contractile force, resulting in hyper-constricted vessels. This leads to hepatic microcirculation dysregulation, which contributes to the progression of diseases such as fibrosis, hepatocellular carcinoma, or viral hepatitis. We hypothesize that the hypercontractile property of activated HSCs is associated with increased isoform expression of NMM II.
Additionally, Dr. Schrum has an active collaboration with Jenkens Biosciences, Inc., to investigate the effects of novel opioid compounds on ameliorating alcohol-induced liver injury.These studies are targeted at understanding the molecular mechanism in HSCs.
Current Graduate Students
Ashley M. Lakner, Doctoral Candidate, Department of Biology, UNC Charlotte
Whitney M. Ellefson, Masters Student, Department of Biology, UNC Charlotte
Past Graduate Students
Kyle J. Thompson, PhD, Postdoc, Department of General Surgery, Carolinas Medical Center
Cathy C. Moore, PhD, Postdoc, Department of General Surgery, Carolinas Medical Center
Stephani A. Day, MS, Cleveland Clinic
Brian W. Cross, MS, MD, Resident, Emory University
Rui Huang, MA
McKillop IH, Schrum LW. 2005. Alcohol and liver cancer. Alcohol 35:195-203.
Zinchenko YS, Schrum LW, Clemens M, Coger RN. 2006. Hepatocyte and Kupffer Cells Co-cultured on Micropatterned Surfaces to Optimize Hepatocyte function. Tissue. Eng. 12:751-761.
McKillop IH, Schrum LW. 2006. Ethanol and Liver Cancer. In Cho CH, Purohit V (eds): Alcohol, Tobacco and Cancer. Basel, Switzerland: S. Karger AG, pp 95-108.
Karaa A*, Thompson KJ*, McKillop IH, Clemens MG, Schrum LW. 2008. S-Adenosyl-L-Methionine (SAMe) Attenuates Oxidative Stress and Hepatic Stellate Cell Activation in an Ethanol-Lipopolysaccharide (LPS)-Induced Fibrotic Rat Model. Shock. 30:197-205
*Both authors contributed equally to this manuscript
Zheng J, Tian Q, Hou W, Watts JA, Schrum LW, Bonkovsky HL. 2008. Tissue-specific Expression of ALA Synthase-1 and Heme Oxygenase-1 and Their Expression in Livers of Rats Chronically Exposed to Ethanol. FEBS Lett. 582:1829-1834.
McKillop IH, Schrum LW. 2009. Role of Alcohol in Liver Carcinogenesis. Semin. Liver Dis. 29:222-232.
McKillop IH, Schrum LW. 2009. Hepatic Ethanol Metabolism. In Schwab M (ed): Encyclopedia of Cancer. 2nd ed. Springer, NY.
Son G, Hines IN, Lindquist J, Schrum LW, Rippe RA. 2009. Inhibition of Phosphatidylinositol 3-Kinase Signaling in Hepatic Stellate Cells Blocks the Progression of Hepatic Fibrosis. Hepatology. 50:1512-1523.
Brandon-Warner E, Sugg JA, Schrum LW, McKillop IH. 2010. Silibinin inhibits ethanol metabolism and ethanol-dependent cell proliferation in rat hepatocellular carcinoma cells. Cancer Lett. 291:120-129.
Lakner AM, Moore CC, Gulledge AA, Schrum LW. 2010. Daily genetic profiling indicates JAK/STAT signaling promotes early hepatic stellate cell transdifferentiation. World J Gastroenterol. 16(40):0000-0000.
Lakner AM, Walling TL, McKillop IH, Schrum LW. Altered aquaporin expression and role in apoptosis during hepatic stellate cell activation. Liv. Int. In press.
Current, Recent and Pending Grant Support
Funding Agency: NIH/NIAAA - R01 AA014891
Title: NFkB-mediated collagen regulation by SAMe in HSCs
Role: Principal investigator
Project Dates: 02/01/05-1/31/11
Goal:To investigate the molecular mechanisms of the antioxidant S-adenosyl-L-methionine on NFkB-mediated collagen regulation in the hepatic stellate cell.
Funding Agency:NIH/NIAAA - R21 AA016858
Title:Effect of alcohol on hepatocellular carcinoma progression in vivo
Role: Co-Investigator (Iain McKillop, PI)
Project Dates:9/20/08 - 8/31/10
Goal: This project hypothesizes that the increased oxidative stress generated due to alcohol metabolism in the liver affects foci progression to HCC directly or via changes in the environment surrounding foci.
Funding Agency:Carolinas Medical Center
Title: Gender and sex steroid hormone effects on developmentally-induced responses in ALD
Role: Co-Principal Investigator (Nury Steuerwald, Yvette Huet, Co-PIs)
Project Dates:04/1/09 - 03/31/10
Goal: The specific goal of this proposal is to determine if the injurious effect of estrogen in alcohol-exposed females is due solely to adult exposure to estrogen or in part to the effects of estrogen on a female imprinted liver.
Funding Agency:NIH/NIAAA - R21 AA018220
Title: Role of Nonmuscle Myosin II Isoforms in HSC Fibrogenesis
Project Dates: 12/01/2009 - 11/30/2011
Goal:To determine the specific cellular function of nonmuscle myosin II isoforms in hepatic stellate cells during alcohol-induced liver injury.
Funding Agency: NIH/NIAMS
Title:Biological Factors Controlling Physical Activity
Project Dates: 07/01/2009 - 06/30/2014
Goal:This project will investigate the genetic basis of physical activity level using advanced genetic techniques.
Funding Agency:Jenken Biosciences, Inc
Title:Studies of a Morphinan Derivative in the Inflammatory Injury Associated with Fatty Liver
Role: Co-PI (with Dr. Mark Clemens)
Project Dates: 07/01/2007 - 06/30/2008
Goal:The purpose of this project is to provide clear proof of concept regarding the ability of Nalmefene to ameliorate hepatic inflammation in a model and to elucidate the molecular mechanisms.
Funding Agency:NIH/NIDDK - R01 DK58503
Title:Engineering aspects of liver support systems.
Role:Co-Investigator (Mark Clemens, PI)
Project Dates: 9/30/01-7/31/06
Goal:To develop a partnership between bioengineers and biologists who will combine their expertise to improve bioartificial liver support systems and to improve liver preservation by using machine perfusion.
Funding Agency: NIH/NIDDK - R01 DK060606
Title: Prostanoids and liver microcirculation in stresses
Role: Co-Investigator (Jian Zhang, PI)
Project Dates:6/1/03 - 5/31/07
Goal: To evaluate the role of constrictor prostanoids in regulation of hepatic microcirculation in cirrhosis and endotoxin-induced sequential stresses.
Funding Agency: NIH/NIAAA - R03 AA14158
Title:Molecular mechanisms of SAMe in hepatic stellate cells
Role: Principal investigator
Project Dates: 9/30/02-8/31/05
Goal: To investigate the molecular mechanisms of the antioxidant S-adenosyl-L-methionine on the activation of NFkB and AP-1, and expression of TNFa, IL-6 and IL-10 in the hepatic stellate cell.
Funding Agency:NIH/NIAID - R01 AI053064
Title:Immunosuppression mediated by tick saliva protein Salp15
Role:Co-Investigator (Juan Anguita, PI)
Project Dates:7/1/03 - 6/30/07
Goal:This project is aimed to assess the mechanism of action of the tick saliva protein Salp15 on CD4+ T cells and the identification and characterization of its receptor.
Funding Agency:NIH - National Research Service Award
Title:Signal transduction in hepatic stellate cells initiated by TGFb1
Goal:To characterize the signal transduction pathway(s) of TGFb1 in primary rat hepatic stellate cells.