MIF in progression and treatment of ALD

Summary

Principal Investigator: Laura E Nagy
Abstract: DESCRIPTION (provided by applicant): Alcohol abuse is a leading cause of morbidity and mortality worldwide. Estimates suggest that in the US 18 million Americans abuse alcohol and that alcoholic liver disease (ALD) affects over 10 million people. Alcohol abuse's deleterious effects on the liver leads to pathologically distinct entities: steatosis, steatohepatitis (ASH), fibrosis and cirrhosis. Fatty liver occurs in up to 90% of alcoholics, but only a subset of heavy drinkers progress to more severe injury. While genetic and environmental risk factors can accelerate progression of ALD in individual heavy drinkers, specific genetic polymorphisms predicting risk for ALD are not well defined. Enhanced inflammation in the liver during ethanol exposure is an important contributor to ALD. Using a pre- clinical mouse model of chronic ethanol exposure, we have identified macrophage migration inhibitory factor (MIF) as an important contributor to ethanol-induced steatosis and inflammation. MIF is a pleiotropic cytokine that enhances the activation of macrophages by increasing inflammatory cytokine production and suppressing activation-induced apoptosis. MIF also counter-regulates the immunosuppressive and anti-inflammatory activities of glucocorticoids. Analysis of the human MIF gene has identified important functional polymorphisms in the promoter region, including a biallelic, CATT(5-8) tetranucleotide repeat at position -794 and a G/C single-nucleotide polymorphism (SNP) at position -173 in the 5'promoter region of MIF. Higher CATT repeats increase MIF expression and are associated with the incidence or severity of a number of inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease and asthma. Here we propose an international collaboration to characterize the role of MIF in ALD. The mechanisms of MIF action in ethanol-induced liver injury will be investigated in pre-clinical mouse models of steatosis and ASH. These data will then be used to move from bench to bedside and determine if genetic variation in MIF expression in human populations predicts the incidence and/or severity of ALD. Further, we will determine whether polymorphisms in the MIF promoter predict the sensitivity of patients to glucocorticoid therapy in ASH. We will generate a unique biobank of DNA samples from: 1) subjects who were identified as heavy drinkers in the DIONYSOS study, which sampled the entire population of two villages in Italy and 2) patients spanning the natural history of ALD, from steatosis to fibrosis and hepatocarcinoma, as well as those with severe ASH, from Barcelona, Spain. Studies in patients with severe ASH will be confirmed in a US cohort of patients in Cleveland Ohio. This international collaboration thus takes a highly innovative, translational approach to investigate mechanisms and therapies for ALD. Results from these studies will facilitate the development of a "personalized" medicine approach to the treatment of ALD, which could allow clinicians to dissect the prevailing pathophysiological mechanisms in an individual patient and adapt therapeutic strategies accordingly. Further, this project will result in the development of a unique and highly informative set of linked genetic and clinical data that can be shared with investigators nationall and internationally for testing specific hypotheses related to the development and treatment of ALD.
Funding Period: 2012-09-01 - 2017-08-31
more information: NIH RePORT

Top Publications

  1. pmc Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis
    Mark A Barnes
    Department of Molecular Medicine, Center for Liver Disease Research, Cleveland, OH, USA
    Hepatology 57:1980-91. 2013

Detail Information

Publications1

  1. pmc Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis
    Mark A Barnes
    Department of Molecular Medicine, Center for Liver Disease Research, Cleveland, OH, USA
    Hepatology 57:1980-91. 2013
    ..Chronic ethanol feeding also sensitized wildtype, but not MIF-/-, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver...

Research Grants30

  1. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  2. Homocysteine, Adiponectin, and Alcoholic Liver Disease
    Zhenyuan Song; Fiscal Year: 2013
    ..We will use the state-of-the-art technologies to investigate this clinically relevant process. ..
  3. Signaling-pathway-based preventative strategies for alcoholic liver disease
    Albert J Fornace; Fiscal Year: 2013
    ..Results will improve approaches to prevent or treat alcoholic liver disease with a solid mechanistic rationale. ..
  4. Genetic risk factors for alcoholic cirrhosis - genome-wide case-control study
    John B Whitfield; Fiscal Year: 2013
    ..Data will be analysed to identify genetic variants that predispose some heavy drinkers to ALC in order to answer the question 'Why do only a minority of alcoholics develop liver cirrhosis?" ..
  5. Alcoholic liver disease: Biochemical, cellular and systemic responses to ethanol
    Laura E Nagy; Fiscal Year: 2013
    ....
  6. North American Mitochondrial Disease Consortium (NAMDC)
    JOHN L THOMPSON; Fiscal Year: 2013
    ....
  7. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  8. IMAGING AUTOIMMUNE DISEASE
    Diane J Mathis; Fiscal Year: 2013
    ..The resulting cross-fertilization will almost certainly continue to result in novel solutions to the persisting problems posed by autoimmune disease. ..
  9. Functional characters of non-coding RNAs in alcoholic liver injury
    Fanyin Meng; Fiscal Year: 2013
    ..abstract_text> ..
  10. Novel molecular and cellular approaches for alcoholism medication development
    Robert A Harris; Fiscal Year: 2013
    ..The PPG has both internal and external advisory board members, providing expert guidance from scientists with a wide range of expertise in drug development and therapeutics. ..
  11. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  12. ETHANOL REGULATION OF KUPFFER CELL SIGNAL TRANSDUCTION
    Laura E Nagy; Fiscal Year: 2013
    ....
  13. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  14. Integrative Metabolic Adaptations to Enviromental and Nutritional Challenge
    MORRIS JAY BIRNBAUM; Fiscal Year: 2013
    ..The projects are supported by three Cores that provide histochemical analysis, generation of genetically modified mice, and their metabolic phenotyping. ..
  15. Role of Dab2 in Fatty Liver Disease
    Norbert Leitinger; Fiscal Year: 2013
    ..Specific Aim 2 will determine the mechanistic basis for Dab2-dependent regulation of inflammation and Specific Aim 3 will examine the hypothesis that Dab2 in myeloid cells is essential for cross talk with NK cells in the liver. ..
  16. Heme oxygenase-1 and alcoholic liver disease
    Laura E Nagy; Fiscal Year: 2013
    ..The studies carried out within our proposed studies will facilitate the development of therapeutic agents to regulate HO-1/CO-regulated pathways will enhance the resolution of inflammation during ALD. ..
  17. Altered Lipid Droplet Trafficking: Role in Alcoholic Fatty Liver Disease
    MARK A MC NIVEN; Fiscal Year: 2013
    ....