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    Pranoti Mandrekar PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMedicine
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-5391
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentTranslational Science

        Overview 
        Narrative

        Pranoti Mandrekar, Ph.D.

         

        Other Affiliation(s):
        Co-Director, Translational Science Program

        Interdisciplinary Graduate Program

        Program In Immunology and Virology
        Graduate School of Biomedical Sciences

         

        INNATE IMMUNE ACTIVATION IN LIVER DISEASES AND CANCER

        Research in my laboratory focuses on understanding the signaling mechanisms involved in innate immune cell activation during liver injury and cancer. The physiological function of the liver is elimination of pathogens and antigens from the blood for which mounting of an immune response is required. To avoid unnecessary activation of the immune system, the liver develops a local immune response followed by induction of peripheral tolerance towards the antigen. When stressful agents such as pathogens or environmental insults challenge the liver for extended periods of time and their elimination is not possible, inflammation and injury follows. The onset of inflammation in the liver is followed by fibrosis, cirrhosis and liver cancer. Thus, studying the mechanisms involved in liver inflammation will provide major insights into pathogenesis of liver disease and progression.

        Using various in vivo and in vitro models, we are studying the role of innate immune signaling pathways, their crosstalk with oxidative stress mechanisms leading to pro-inflammatory cytokine production. We are also focusing on investigating the role of chemokine responses and their effect on recruitment of bone-marrow derived cells and immune cells in the liver during development and progression of liver disease. Recent studies initiated in our lab focus on the impact of alcohol drinking on breast and liver cancer. Th main areas of focus are:

        1) Oxidative stress and Inflammation in host defense and liver diseases

        Characterization of an interplay of immune and oxidative stress related mechanisms involved in mediating the effects of acute and chronic alcohol consumption, and epigenetic pathways altered in chronic liver diseases using alcoholic and non-alcoholic liver disease models are being studied. We identified a pathogenic role for stress mediated transcription factor HSF1 and its target gene, hsp90 and hsp70 in innate immune cells resulting in regulation of inflammatory responses. Using molecular and targeted translational approaches we are currently evaluating hsp90 and hsp70 as a therapeutic targets in manipulation of macrophage function in host defense and liver diseases such as alcoholic liver disease and fibrosis.

        2) Chemokines and importance of immune liver cell types in liver injury

        In this project, the dynamic role of immune cells and bone marrow derived hematopoietic cells and their cross talk with other liver cell types in promoting liver diseases is being investigated. Liver macrophages, dendritic cells, NK and NKT cells play an important function in development and progression of liver disease. We propose to unravel the role of chemokinesin recruitment of immune cells in the liver and modulate chronic liver injury. Specifically, recent studies in our laboratory have identified a significant role for a CC-chemokine, monocyte chemoattractant protein -1 (MCP-1) in induction of fatty liver disease. Other chemokines and chemokine receptors are also being explored to determine the role of MCP-1 in mediating inflammatory processes leading to alcoholic liver injury.

        3) Alcohol and breast Cancer

        Heavy alcohol consumption increases the risk of human breast cancer by up to 50%  and is associated with a worse outcome and a higher incidence of relapse. Initiation and progression of breast cancer is linked to a local inflammatory cytokine environment and alcohol, a modulator of the proinflammatory response, likely affects the breast tissue.   Cancer and the tumor microenvironment are characterized by an imbalance in oxidative stress and protein homeostasis. Alcohol activates stress-induced heat shock transcription factor (HSF1) and its target genes, heat shock proteins (hsps) in macrophages and in breast cancer epithelial cells. Here we hypothesize that prolonged alcohol via activation of stress mediated HSF1 or target hsps that serve as chaperones for signaling pathway intermediates in immune activation orchestrates an inflammatory microenvironment conducive to initiation and progression of human breast cancer in vivo. We will use a combination of in vitro cell culture studies and novel mouse model of human breast cancer ex-plants to determine the effects of chronic alcohol consumption on human cancer growth, progression and metastasis. 

         



        Rotation Projects

        Potential Rotation Projects

        1. Expression and function of molecular chaperones such as hsp70 and hsp90 in liver disease: Determine the expression of hsp70 and hsp90 in different cell types of the liver during acute and chronic liver injury using in vivo and in vitro models. Subsequently, we will test the relevance of the expression of these proteins in activation of intracellular signaling molecules involved in induction of pro-inflammatory cytokines.
        2. Role of MCP-1 in induction of fatty liver disease: CC-chemokines particularly MCP-1, is significantly increased in serum as well as in the liver parenchyma in patients with alcoholic hepatitis. We will test the role of MCP-1 in induction of fatty acid synthesis or metabolism in the alcoholic liver. Our studies will also investigate the role of MCP-1 directed migration of immune cells in the liver contributing to injury.


        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Muralidharan S, Ambade A, Fulham MA, Deshpande J, Catalano D, Mandrekar P. Moderate Alcohol Induces Stress Proteins HSF1 and hsp70 and Inhibits Proinflammatory Cytokines Resulting in Endotoxin Tolerance. J Immunol. 2014 Aug 15; 193(4):1975-87.
          View in: PubMed
        2. Muralidharan S, Mandrekar P. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J Leukoc Biol. 2013 Dec; 94(6):1167-84.
          View in: PubMed
        3. Ambade A, Catalano D, Lim A, Mandrekar P. Inhibition of heat shock protein (molecular weight 90 kDa) attenuates proinflammatory cytokines and prevents lipopolysaccharide-induced liver injury in mice. Hepatology. 2012 May; 55(5):1585-95.
          View in: PubMed
        4. Ambade A, Mandrekar P. Oxidative stress and inflammation: essential partners in alcoholic liver disease. Int J Hepatol. 2012; 2012:853175.
          View in: PubMed
        5. Mandrekar P, Ambade A, Lim A, Szabo G, Catalano D. An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology. 2011 Dec; 54(6):2185-97.
          View in: PubMed
        6. Mandrekar P. Epigenetic regulation in alcoholic liver disease. World J Gastroenterol. 2011 May 28; 17(20):2456-64.
          View in: PubMed
        7. Nath B, Levin I, Csak T, Petrasek J, Mueller C, Kodys K, Catalano D, Mandrekar P, Szabo G. Hepatocyte-specific hypoxia-inducible factor-1a is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology. 2011 May; 53(5):1526-37.
          View in: PubMed
        8. Csak T, Velayudham A, Hritz I, Petrasek J, Levin I, Lippai D, Catalano D, Mandrekar P, Dolganiuc A, Kurt-Jones E, Szabo G. Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol. 2011 Mar; 300(3):G433-41.
          View in: PubMed
        9. Petrasek J, Dolganiuc A, Csak T, Nath B, Hritz I, Kodys K, Catalano D, Kurt-Jones E, Mandrekar P, Szabo G. Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells. Hepatology. 2011 Feb; 53(2):649-60.
          View in: PubMed
        10. Bala S, Marcos M, Kodys K, Csak T, Catalano D, Mandrekar P, Szabo G. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem. 2011 Jan 14; 286(2):1436-44.
          View in: PubMed
        11. Petrasek J, Mandrekar P, Szabo G. Toll-like receptors in the pathogenesis of alcoholic liver disease. Gastroenterol Res Pract. 2010; 2010.
          View in: PubMed
        12. Szabo G, Mandrekar P. Focus on: alcohol and the liver. Alcohol Res Health. 2010; 33(1):87-96.
          View in: PubMed
        13. Dolganiuc A, Petrasek J, Kodys K, Catalano D, Mandrekar P, Velayudham A, Szabo G. MicroRNA expression profile in Lieber-DeCarli diet-induced alcoholic and methionine choline deficient diet-induced nonalcoholic steatohepatitis models in mice. Alcohol Clin Exp Res. 2009 Oct; 33(10):1704-10.
          View in: PubMed
        14. Mandrekar P, Bala S, Catalano D, Kodys K, Szabo G. The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes. J Immunol. 2009 Jul 15; 183(2):1320-7.
          View in: PubMed
        15. Mandrekar P, Szabo G. Signalling pathways in alcohol-induced liver inflammation. J Hepatol. 2009 Jun; 50(6):1258-66.
          View in: PubMed
        16. Velayudham A, Dolganiuc A, Ellis M, Petrasek J, Kodys K, Mandrekar P, Szabo G. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology. 2009 Mar; 49(3):989-97.
          View in: PubMed
        17. Szabo G, Mandrekar P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res. 2009 Feb; 33(2):220-32.
          View in: PubMed
        18. Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology. 2008 Oct; 48(4):1224-31.
          View in: PubMed
        19. Hritz I, Velayudham A, Dolganiuc A, Kodys K, Mandrekar P, Kurt-Jones E, Szabo G. Bone marrow-derived immune cells mediate sensitization to liver injury in a myeloid differentiation factor 88-dependent fashion. Hepatology. 2008 Oct; 48(4):1342-7.
          View in: PubMed
        20. Mandrekar P, Catalano D, Jeliazkova V, Kodys K. Alcohol exposure regulates heat shock transcription factor binding and heat shock proteins 70 and 90 in monocytes and macrophages: implication for TNF-alpha regulation. J Leukoc Biol. 2008 Nov; 84(5):1335-45.
          View in: PubMed
        21. Norkina O, Dolganiuc A, Catalano D, Kodys K, Mandrekar P, Syed A, Efros M, Szabo G. Acute alcohol intake induces SOCS1 and SOCS3 and inhibits cytokine-induced STAT1 and STAT3 signaling in human monocytes. Alcohol Clin Exp Res. 2008 Sep; 32(9):1565-73.
          View in: PubMed
        22. Szabo G, Mandrekar P. Human monocytes, macrophages, and dendritic cells: alcohol treatment methods. Methods Mol Biol. 2008; 447:113-24.
          View in: PubMed
        23. Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation. Semin Liver Dis. 2007 Nov; 27(4):339-50.
          View in: PubMed
        24. Mandrekar P. Signaling mechanisms in alcoholic liver injury: role of transcription factors, kinases and heat shock proteins. World J Gastroenterol. 2007 Oct 7; 13(37):4979-85.
          View in: PubMed
        25. Dolganiuc A, Norkina O, Kodys K, Catalano D, Bakis G, Marshall C, Mandrekar P, Szabo G. Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterology. 2007 Nov; 133(5):1627-36.
          View in: PubMed
        26. Szabo G, Mandrekar P, Oak S, Mayerle J. Effect of ethanol on inflammatory responses. Implications for pancreatitis. Pancreatology. 2007; 7(2-3):115-23.
          View in: PubMed
        27. Mandrekar P, Jeliazkova V, Catalano D, Szabo G. Acute alcohol exposure exerts anti-inflammatory effects by inhibiting IkappaB kinase activity and p65 phosphorylation in human monocytes. J Immunol. 2007 Jun 15; 178(12):7686-93.
          View in: PubMed
        28. Norkina O, Dolganiuc A, Shapiro T, Kodys K, Mandrekar P, Szabo G. Acute alcohol activates STAT3, AP-1, and Sp-1 transcription factors via the family of Src kinases to promote IL-10 production in human monocytes. J Leukoc Biol. 2007 Sep; 82(3):752-62.
          View in: PubMed
        29. Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M, Szabo G. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006 Nov 15; 177(10):6758-68.
          View in: PubMed
        30. Drechsler Y, Dolganiuc A, Norkina O, Romics L, Li W, Kodys K, Bach FH, Mandrekar P, Szabo G. Heme oxygenase-1 mediates the anti-inflammatory effects of acute alcohol on IL-10 induction involving p38 MAPK activation in monocytes. J Immunol. 2006 Aug 15; 177(4):2592-600.
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        31. Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology. 2006 Aug; 44(2):287-98.
          View in: PubMed
        32. Velayudham A, Hritz I, Dolganiuc A, Mandrekar P, Kurt-Jones E, Szabo G. Critical role of toll-like receptors and the common TLR adaptor, MyD88, in induction of granulomas and liver injury. J Hepatol. 2006 Dec; 45(6):813-24.
          View in: PubMed
        33. Oak S, Mandrekar P, Catalano D, Kodys K, Szabo G. TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes. J Immunol. 2006 Jun 15; 176(12):7628-35.
          View in: PubMed
        34. Crews FT, Bechara R, Brown LA, Guidot DM, Mandrekar P, Oak S, Qin L, Szabo G, Wheeler M, Zou J. Cytokines and alcohol. Alcohol Clin Exp Res. 2006 Apr; 30(4):720-30.
          View in: PubMed
        35. Dolganiuc A, Bakis G, Kodys K, Mandrekar P, Szabo G. Acute ethanol treatment modulates Toll-like receptor-4 association with lipid rafts. Alcohol Clin Exp Res. 2006 Jan; 30(1):76-85.
          View in: PubMed
        36. Mandrekar P, Catalano D, White B, Szabo G. Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Alcohol Clin Exp Res. 2006 Jan; 30(1):135-9.
          View in: PubMed
        37. Szabo G, Velayudham A, Romics L, Mandrekar P. Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4. Alcohol Clin Exp Res. 2005 Nov; 29(11 Suppl):140S-145S.
          View in: PubMed
        38. Romics L, Dolganiuc A, Velayudham A, Kodys K, Mandrekar P, Golenbock D, Kurt-Jones E, Szabo G. Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni- bacterium acnes. J Leukoc Biol. 2005 Dec; 78(6):1255-64.
          View in: PubMed
        39. Mandrekar P, Pruett S, Arteel G, Thiele G, Szabo G. RSA 2004: combined basic research satellite symposium - session two: toll-like receptors and organ damage. Alcohol Clin Exp Res. 2005 Sep; 29(9):1744-8.
          View in: PubMed
        40. Szabo G, Weinman SA, Gao B, Polyak SJ, Mandrekar P, Thiele GM. RSA 2004: combined basic research satellite symposium - session four: hepatitis virus and alcohol interactions in immunity and liver disease. Alcohol Clin Exp Res. 2005 Sep; 29(9):1753-7.
          View in: PubMed
        41. Hoek J, Thiele GM, Klassen LW, Mandrekar P, Zakhari S, Cook RT, Ray NB, Happel KI, Kolls JK, Kovacs EJ, Szab G. RSA 2004: combined basic research satellite symposium-mechanisms of alcohol-mediated organ and tissue damage: inflammation and immunity and alcohol and mitochondrial metabolism: at the crossroads of life and death session one: alcohol, cellular and organ damage. Alcohol Clin Exp Res. 2005 Sep; 29(9):1735-43.
          View in: PubMed
        42. Romics L, Mandrekar P, Kodys K, Velayudham A, Drechsler Y, Dolganiuc A, Szabo G. Increased lipopolysaccharide sensitivity in alcoholic fatty livers is independent of leptin deficiency and toll-like receptor 4 (TLR4) or TLR2 mRNA expression. Alcohol Clin Exp Res. 2005 Jun; 29(6):1018-26.
          View in: PubMed
        43. Romics L, Dolganiuc A, Kodys K, Drechsler Y, Oak S, Velayudham A, Mandrekar P, Szabo G. Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands by P. acnes involves up-regulation of MD-2 in mice. Hepatology. 2004 Sep; 40(3):555-64.
          View in: PubMed
        44. Mandrekar P, Catalano D, Dolganiuc A, Kodys K, Szabo G. Inhibition of myeloid dendritic cell accessory cell function and induction of T cell anergy by alcohol correlates with decreased IL-12 production. J Immunol. 2004 Sep 1; 173(5):3398-407.
          View in: PubMed
        45. Romics L, Kodys K, Dolganiuc A, Graham L, Velayudham A, Mandrekar P, Szabo G. Diverse regulation of NF-kappaB and peroxisome proliferator-activated receptors in murine nonalcoholic fatty liver. Hepatology. 2004 Aug; 40(2):376-85.
          View in: PubMed
        46. Szabo G, Dolganiuc A, Mandrekar P, White B. Inhibition of antigen-presenting cell functions by alcohol: implications for hepatitis C virus infection. Alcohol. 2004 Jul; 33(3):241-9.
          View in: PubMed
        47. Szabo G, Catalano D, White B, Mandrekar P. Acute alcohol consumption inhibits accessory cell function of monocytes and dendritic cells. Alcohol Clin Exp Res. 2004 May; 28(5):824-8.
          View in: PubMed
        48. Dolganiuc A, Kodys K, Kopasz A, Marshall C, Mandrekar P, Szabo G. Additive inhibition of dendritic cell allostimulatory capacity by alcohol and hepatitis C is not restored by DC maturation and involves abnormal IL-10 and IL-2 induction. Alcohol Clin Exp Res. 2003 Jun; 27(6):1023-31.
          View in: PubMed
        49. Dolganiuc A, Kodys K, Kopasz A, Marshall C, Do T, Romics L, Mandrekar P, Zapp M, Szabo G. Hepatitis C virus core and nonstructural protein 3 proteins induce pro- and anti-inflammatory cytokines and inhibit dendritic cell differentiation. J Immunol. 2003 Jun 1; 170(11):5615-24.
          View in: PubMed
        50. Mandrekar P, Bellerose G, Szabo G. Inhibition of NF-kappa B binding correlates with increased nuclear glucocorticoid receptor levels in acute alcohol-treated human monocytes. Alcohol Clin Exp Res. 2002 Dec; 26(12):1872-9.
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        51. Mandrekar P, Dolganiuc A, Bellerose G, Kodys K, Romics L, Nizamani R, Szabo G. Acute alcohol inhibits the induction of nuclear regulatory factor kappa B activation through CD14/toll-like receptor 4, interleukin-1, and tumor necrosis factor receptors: a common mechanism independent of inhibitory kappa B alpha degradation? Alcohol Clin Exp Res. 2002 Nov; 26(11):1609-14.
          View in: PubMed
        52. Drechsler Y, Chavan S, Catalano D, Mandrekar P, Szabo G. FcgammaR cross-linking mediates NF-kappaB activation, reduced antigen presentation capacity, and decreased IL-12 production in monocytes without modulation of myeloid dendritic cell development. J Leukoc Biol. 2002 Oct; 72(4):657-67.
          View in: PubMed
        53. Szabo G, Mandrekar P. Ethanol-mediated regulation of transcription factors in immunocompetent cells. Front Biosci. 2002 May 1; 7:a80-9.
          View in: PubMed
        54. Mandrekar P, Catalano D, Szabo G. Inhibition of lipopolysaccharide-mediated NFkappaB activation by ethanol in human monocytes. Int Immunol. 1999 Nov; 11(11):1781-90.
          View in: PubMed
        55. Mandrekar P, Catalano D, Szabo G. Alcohol-induced regulation of nuclear regulatory factor-kappa beta in human monocytes. Alcohol Clin Exp Res. 1997 Sep; 21(6):988-94.
          View in: PubMed
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