Robert A. Mitchell, Ph.D.

Education:

B.S. in Immunology, University of Iowa School of Medicine, Iowa City, IA, 1989
Ph.D. in Experimental Pathology, Albany Medical College, Albany, New York, 1998
Postdoctoral Fellowship, Picower Institute for Medical Research, Manhasset, NY, 1998-01

Curriculum Vitae

Current Positions:

Professor, Department of Medicine, University of Louisville
Associate Professor, Department of Biochemistry & Molecular Biology, University of Louisville – Joint Appointment
Associate Faculty Member, Department of Microbiology & Immunology, University of Louisville

Contact Information:

Robert A. Mitchell, Ph.D.
University of Louisville
Clinical and Translational Research Building
505 S. Hancock St.
Suite 404
Louisville, KY 40202
(502) 852-7698
(502) 852-3661

Email: robert.mitchell@louisville.edu

Research Description:

Dr. Robert A. Mitchell is a tenured Professor in the Department of Surgery and a member of the Division of Immunotherapy at the University of Louisville. He has joint/associate appointments in the Departments of Microbiology & Immunology and Biochemistry & Molecular Genetics. He has received funding and/or is currently funded by the National Institutes of Health (NIH), the Jewish Heritage Foundation, the American Lung Association, the Kentucky Lung Cancer Research Program and the UofL School of Medicine. His research is primarily focused on the study of immune tolerance in tumor biology. Specifically, his work focuses on the macrophage migration inhibitory factor (MIF) family of cytokines and their independent and coordinated influences on myeloid lineage-dependent T cell suppressive mechanisms which govern tumor-associated immune evasion and subsequent disease progression. He and his laboratory have developed numerous patented pharmaceutical agents that are designed to treat malignant and nonmalignant diseases and they are currently evaluating whether these compounds have a specific role in governing MIF-dependent mitochondrial homeostasis that dictates myeloid cell immune suppression.

Literature Cited:

  1. K.W. Harris, R.A. Mitchell and J.C. Winkelmann (1991) Ligand Binding Properties of the Human Erythropoietin Receptor Extracellular Domain Expressed in E. Coli.  J. Biol. Chem. (267) 15205-15209. PMID: 1321832
  2. J. Bernhagen, T. Calandra, R.A. Mitchell, S.B. Martin, K.J. Tracy, W. Voelter, K.R. Manogue, A. Cerami and R. Bucala (1993) Macrophage migration inhibition factor (MIF) is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature (365) 756-759. PMID: 8413654
  3. T. Calandra, J. Bernhagen, R.A. Mitchell, and R. Bucala (1994) The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J. Exp. Med. (79)6 1895-1902. PMID: 8915715
  4. J. Bernhagen, R.A. Mitchell, T. Calandra, W. Voelter, A Cerami, and R. Bucala (1994) Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry (33)47 14144-14155. PMID: 7947826
  5. R.A. Mitchell, M. Bacher, J. Bernhagen, T. Pushkarskaya, M.F. Seldin and R. Bucala (1995) Cloning and characterization of the gene for mouse macrophage migration inhibitory factor (MIF). J. Immunol. (154)8 3863-3870. PMID: 7706726
  6. R. Bucala, R.A. Mitchell, K. Arnold, T. Innerarity, H. Vlassara and A. Cerami (1995) Identification of the major site of apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipoprotein receptor. J. Biol. Chem. (270)18 10828-10832. PMID: 7738020
  7. B. Sherry, G. Zybarth, M. Alfano L. Dubrovsky, R.A. Mitchell, D. Rich, P. Ulrich, R. Bucala, A. Cerami and  M. Bukrinsky (1998) Role of cyclophilin A in the uptake of HIV-1 by macrophages and T lymphocytes. Proc. Natl. Acad. Sci. 95(4) 1758-      1763. PMID: 9465090
  8. J. Chesney, R.A. Mitchell, F. Benigni, M. Bacher, L. Spiegel, Y. Al Abed, J.H. Han,  C. Metz and R. Bucala (1999) An inducible gene product for 6 phosphofructo-2 kinase with an AU rich instability element:  Role in tumor cell glycolysis and the Warburg effect. Proc. Natl. Acad. Sci. 96(6) 3047 3052. PMID: 10077634
  9. R.A. Mitchell, C. Metz, T. Peng and R. Bucala. (1999) Sustained MAP kinase and cPLA2 activation by macrophage inhibitory factor (MIF): Regulatory role in cell proliferation and glucocorticoid action. J. Biol. Chem. 274 18100-18106. PMID: 10364264
  10. R.A. Mitchell and R. Bucala (2000) Tumor growth promoting properties of macrophage migration inhibitory factor (MIF). Semin. Cancer Biol. 10(5):359 66. PMID: 11100884
  11. A.V. Sampey, P.H. Hall, R.A. Mitchell, C.N. Metz and E.F. Morand (2001) Regulation of synoviocyte phospholipase A2 and cyclooxygenase-2 by macrophage migration inhibitory factor. Arthritis Rheum. 44(6) 1273 80. PMID: 11407686
  12. P.D. Senter, Y. Al-Abed, C.N. Metz, F. Benigni, R.A. Mitchell, C.G. Gartner, S.D. Nelson, G.J. Todaro and R. Bucala (2002) Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites. Proc. Natl. Acad. Sci.  99(1):144-149. PMID: 11773615
  13. R.A. Mitchell, H. Liao, J. Chesney, G. Fingerle-Rowson, J. Baugh, J. David and R. Bucala (2002) MIF sustains macrophage pro-inflammatory function by inhibiting p53: Regulatory role in the innate immune response. Proc. Natl. Acad. Sci. 99(1):345-350. PMID: 11756671
  14. A. Dios, R.A. Mitchell, B. Aljabari, J. Lubetsky, K.A. O'Connor, H. Liao, P.D. Senter, K.R. Manogue, E. Lolis, C.N. Metz, R. Bucala, D.J. Callaway and Y. Al-Abed (2002) Inhibition of MIF bioactivity by rational design of pharmacological inhibitors of MIF tautomerase activity. J. Med. Chem. 45(12):2410-2416. PMID: 12036350
  15. J.B. Lubetsky, A. Dios, J. Han, B. Aljabari, B. Ruzsicska, R.A. Mitchell, E. Lolis and Y. Al-abed (2002) The tautomerase activity of MIF is a potential target for discovery of novel anti-inflammatory agents. J. Biol. Chem. 277(28):24976-82. PMID: 11997397
  16. T. Atsumi, J. Chesney, C. Metz, L. Leng, S. Donnelly Z. Makita, R.A. Mitchell, and R. Bucala. (2002) High Expression of Inducible 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in Human Cancers. Cancer Res. 62(20):5881-7. PMID: 12384552
  17. H. Liao, R. Bucala and R.A. Mitchell (2003) Adhesion-dependent signaling by macrophage migration inhibitory factor (MIF). J. Biol. Chem. 278(1):76-81. PMID: 12297513
  18. D. Lacey, A. Sampey, R.A. Mitchell, L. Santos, M. Leech and E. Morand (2003) Control of fibroblast-like synoviocyte proliferation by macrophage migration inhibitory factor. Arthritis Rheum. 48(1):103-9. PMID: 12528110
  19. O. Petrenko, G. Fingerle-Rowson, T. Peng, R.A. Mitchell and C.N. Metz. (2003) MIF-deficiency is associated with altered cell growth and reduced susceptibility to Ras-mediated transformation. J. Biol. Chem. 278(13):11078-11085. PMID: 12538581
  20. B. Rendon-Mitchell, M. Ochani, J. Li, J. Han, H. Wang, S. Susarla, C. Czura, R.A. Mitchell, A. Sama, K. Tracey and H. Wang (2003) IFN induces HMGB1 release partially through a TNF-dependent mechanism. J. Immunol. 170(7)3890-3897. PMID: 12646658
  21. L. Leng, C. Metz, Y. Fang, J. Xu, S. Donnelly, J. Baugh, T. Delohery, Y. Chen, R.A. Mitchell and R.  Bucala (2003) MIF signal transduction initiated by binding to CD74. J. Exp. Med. 197(11):1467-1476. PMID: 12782713
  22. G. Fingerle-Rowson, O. Petrenko, C.N. Metz, T.G Forsthuber, R.A. Mitchell, R. Huss, U. Moll, W. Muller and R. Bucala (2003) The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting. Proc Natl Acad Sci U S A. 100(16):9354-9359. PMID: 12878730
  23. J.D. Swant, B.E. Rendon, M. Symons and R.A. Mitchell (2005) Rho GTPase-dependent signaling is required for MIF-mediated expression of cyclin D1. J. Biol. Chem. 280(24):23066-23072. PMID: 15840582
  24. M.A. McDevitt, J. Xie, G. Shanmugasundaram, J. Griffith, A. Liu, C. McDonald, P. Thuma, V.R. Gordeuk, C.N. Metz, R.A. Mitchell, J. Keefer, J.R. David, L. Leng and R. Bucala (2006) A critical role for the host mediator, MIF, in the pathogenesis of malarial anemia.  J. Exp. Med. 15;203(5):1185-96. PMID: 16636133
  25. M. Winner, A.C. Koong, B.E. Rendon, W. Zundel and R.A. Mitchell (2007) Amplification of tumor hypoxic responses by MIF-dependent HIF stabilization. Cancer Res. 67(1):186-193. PMID: 17210698
  26. T. Atsumi, Y.R. Cho, L. Leng, C. McDonald, T. Yu, C. Danton, E.G. Hong, R.A. Mitchell, C. Metz, H. Hiwa, J. Takeuchi, S. Onodera, T. Umino, J.K. Kim and R. Bucala (2007) The pro-inflammatory cytokine MIF regulates glucose metabolism during systemic inflammation. J Immunol. 2007 179(8):5399-5406. PMID: 17911626
  27. B.E. Rendon, I. Teneng, M. Zhao, M. Winner, Y. Al-Abed and R.A. Mitchell (2007) Regulation of human lung adenocarcinoma cell migration and invasion by MIF. J. Biol. Chem. 282:29910-18. PMID: 17709373
  28. A.M. Coleman, D. Xin, M. Zhao, M.W. Qian, R. Bucala, B.E. Rendon and R.A. Mitchell (2008) Cooperative Regulation of NSCLC Angiogenic Potential by MIF and its Homolog, D-Dopachrome Tautomerase. J. Immunol. 181(4):2330-7. PMID: 18684922
  29. D. Kamir, S. Zierow, L. Leng, Y. Cho, Y. Diaz, J. Griffith, C. McDonald, M. Merk, R.A. Mitchell, J. Trent, Y. Chen, Y.K. Kwong, H. Xiong, J. Vermeire, M. Cappello, D. McMahon-Pratt, J. Walker, J. Bernhagen, E. Lolis E, R. Bucala (2008) A Leishmania ortholog of macrophage migration inhibitory factor modulates host macrophage responses. J Immunol. 180(12):8250-61. PMID: 18523291
  30. M. Winner, J. Meier, S. Zierow, B.E. Rendon, G. Crichlow, R. Riggs, R. Bucala, L. Leng, N. Smith, E. Lolis, J.O. Trent and R.A. Mitchell (2008) A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells. Cancer Res. 68(18):7253-7. PMID: 18794110
  31. BE Rendon, SS Willer, W. Zundel and R.A. Mitchell (2009) Mechanisms of MIF-dependent tumor-microenvironmental adaptation. Exp Mol Pathol. 86(3):180-5. PMID: 19186177
  32. M. Merk, J. Baugh, S. Zierow, L. Leng, U. Pal, S.J. Lee, A.D. Ebert, Y. Mizue, J.O. Trent, R.A. Mitchell, W. Nicke, PB Kavathas, J. Bernhagen and R. Bucala (2009) The Golgi-associated protein p115 mediates the secretion of macrophage migration inhibitory factor. J Immunol. 182(11):6896-906. PMID: 19454686
  33. M. Gadjeva, J. Nagashima, T. Zaidi, R.A. Mitchell and Pier GB (2010) Inhibition of macrophage migration inhibitory factor ameliorates ocular Pseudomonas aeruginosa-induced keratitis. PLoS Pathog. 6(3):e1000826. PMID: 20361053
  34. D. Xin, B.E. Rendon, M. Zhao, M. Winner, A. Coleman and R.A. Mitchell (2010) The MIF homolog, D-dopachrome tautomerase (D-DT), promotes COX-2 expression through -catenin-dependent and independent mechanisms. Mol. Cancer Res. 12:1601-1609. PMID: 21071513
  35. M. Tarnowski, K. Grymula, R. Liu, J. Tarnowska, J. Drukala, J. Ratajczak, R.A. Mitchell, M.Z. Ratajczak and M. Kucia (2010) MIF is secreted by rhabdomyosarcoma cells, modulates tumor metastasis by binding to CXCR4 and CXCR7 receptors and inhibits recruitment of cancer-associated fibroblasts. Mol Cancer Res. 8(10):1328-43. PMID: 20861157
  36. K. Yaddanapudi*, R.A. Mitchell*, Putty K, Willer S, Sharma RK, Yan J, Bodduluri H, Eaton JW (2012) Vaccination with embryonic stem cells protects against lung cancer: is a broad-spectrum prophylactic vaccine against cancer possible?  PLoS One. 7(7):e42289. PMID: 22860107 *Equal Contribution
  37. M. Merck, R.A. Mitchell and R. Bucala (2012) D-dopachrome tautomerase (D-DT or MIF-2): Doubling the MIF cytokine family. Cytokine 59(1):10-17. PMID: 22507380
  38. S.E. Brock, B.E. Rendon, K. Yaddanapudi and R.A. Mitchell (2012) Negative regulation of AMPK activity by MIF family members in NSCLC. J. Biol. Chem. 287(45):37917-25. PMID: 22988252
  39. K. Yaddanapudi, R.A. Mitchell and J.W. Eaton (2013) Cancer vaccines: Looking to the future. Oncoimmunology 2(3):e23403. PMID: 23802081
  40. K. Yaddanapudi, K. Putty, B.E. Rendon, A. Satoskar, A. Lasnik, J.W. Eaton and R.A. Mitchell (2013) Control of tumor-associated macrophage alternative activation by MIF. J Immunol. 190(6):2984-93. PMID: 23390297
  41. M. Dwyer, Q. Shan, S. D’Ortona, R. Maurer, R.A. Mitchell, H. Olesen, S. Thiel, J. Huebner and M. Gadjeva (2014) Cystic Fibrosis Sputum DNA has NET-like characteristics. Journal of Innate Immunity 6(6):765-79. PMID: 24862346
  42. S.E. Brock, B.E. Rendon, D. Xin, K. Yaddanapudi and R.A. Mitchell (2014) Cooperative antagonism of p53 stabilization and activity by MIF family members in lung adenocarcinoma. PLOS One 16;9(6):e99795 PMID: 24932684
  43. R.A. Mitchell and K. Yaddanapudi (2014) Stromal-dependent tumor promotion by MIF family members. Cell Signal. 26(12):2969-2978. PMID: 25277536
  44. K. Yaddanapudi, K. Putty, B.E. Rendon, A. Satoskar, A. Lasnik, J.W. Eaton and R.A. Mitchell (2013) Control of tumor-associated macrophage alternative activation by MIF. J Immunol. 190(6):2984-93. PMCID: PMC3593945
  45. R.A. Mitchell and K. Yaddanapudi (2014) Stromal-dependent tumor promotion by MIF family members. Cell Signal. 26(12):2969-2978. PMID: 25277536
  46. K. Yaddanapudi, B.E. Rendon, G. Lamont, E.J. Kim, N. Al Rayyan, J. Richie, S. Albeituni, S. Waigel, A. Wise and R.A. Mitchell (2016) MIF controls myeloid-derived immunosuppression in human malignant melanoma. Cancer Immunol. Res. 4(2):101-12. PMID: 26603621
  47. S. Waigel, B.E. Rendon, G. Lamont, J. Richie, R.A. Mitchell* and K. Yaddanapudi* (2016) MIF inhibition reverts the gene expression profile of human melanoma cell line-induced MDSCs to normal monocytes. Genom Data. 7:240-2. PMID: 26981417 *Corresponding Authors
  48. J. Chesney, R.A. Mitchell* and K. Yaddanapudi* (2017) Myeloid-derived suppressor cells - a new therapeutic target to overcome resistance to cancer immunotherapy. J. Leuk. Biol. 102(3):727-740. PMID: 28546500 *Corresponding
  49. Rizzo M.B., de Carvalho M, Kim E.J., Rendon B.E., Noe J.T., Wise-Mitchell AD and R.A. Mitchell (2018) Oral squamous carcinoma cells promote macrophage polarization in an MIF‐dependent manner. Quarterly Journal of Medicine 111(11):769-778. PMID: 30016493
  50. Noe J.T. and R. A. Mitchell (2019) Tricarboxylic acid cycle metabolites in the control of macrophage activation and effector phenotypes. J. of Leuk. Biol. 106(2):359-367 PMID: 30768807
  51. Noe, J.T. and R.A. Mitchell (2020) MIF-dependent control of tumor immunity. Front Immunol. 11:609948 PMID: 33324425
  52. Guo, Y., Lu, X., Chen, Y, Rendon, B., Mitchell, R.A., Cuatrecasas, M., Postigo, A., Li, Y., Cortes, M. and D.C. Dean (2021) Zeb1 Induces Immune Checkpoints to Form an Immunosuppressive Envelope Around Invading Cancer Cells. Sci. Adv. 7(21) PMID: 34020945
  53. Morrissey S, Zhang F, Ding C, Yang C, Wang Z, Hu X, Fang Y, Fox M, Zhang HG, Guo H, Tieri D, Kong M, Watson CT, Mitchell RA, Zhang X, Huang J, McMasters KM, and Yan J. (2021) Tumor-derived Exosomes Drive Immunosuppressive Macrophages in a Pre-metastatic Niche through Glycolytic Dominant Metabolic Reprogramming. Cell Metabolism (In Press).
  54. Noe, J.T., Rendon, B.E, Geller, A.E., Morrissey, S.M., Conroy, L.R., Kim E.J., Wise‐Mitchell A., Barbosa de Souza Rizzo M., Young, L.E, Bruntz, R.C., Affronti, H.C., Baby, B.V, McMasters, K.M., Clem, B.F., Yan, Y., Wellen, K.E., Sun, R.C. Sun, and R.A. Mitchell (2021) Lactate supports a metabolic-epigenetic link in macrophage polarization. Sci. Adv. (In Press)

NIH Bibliography