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Joshua Munger

TitleAssociate Professor
InstitutionSchool of Medicine and Dentistry
DepartmentBiochemistry and Biophysics
AddressUniversity of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester NY 14642
Other Positions
TitleAssociate Professor
InstitutionSchool of Medicine and Dentistry
DepartmentMicrobiology and Immunology

 
 Overview
Mechanisms of Pathogenic Metabolic Manipulation

Both cancerous cells and viruses depend on the metabolic resources provided by the host to supply the energy and biochemical building blocks necessary for their replication. Many anti-viral and anti-cancer compounds, such as nucleotide analogs, target these parasites' utilization of cellular metabolic resources and have proven to be clinically successful. Despite these successes, very little is known about the mechanisms governing the pathogenic manipulation of the small molecule metabolic network. Our laboratory's goal is to elucidate these mechanisms and thereby identify potential therapeutic targets to block cancer- and virally-associated disease.
A major focus of our laboratory is on human cytomegalovirus (HCMV), a herpes virus, which is the leading cause of congenital viral infection, occurring in approximately %1 of all live births. Congenital HCMV infection results in central nervous system damage in the majority of symptomatic newborns. HCMV infection also poses a serious health risk to immunosuppressed individuals, such as the elderly, and patients receiving immunosuppressive chemotherapy, including cancer patients, transplant recipients, and AIDS patients.
Another major focus in my laboratory is to elucidate novel metabolic activities induced by the transformation of cells from normal to cancerous. It has been known for decades that this cancerous transformation induces gross metabolic changes. However, many questions remain about the specific activities induced and the upstream mechanisms that are responsible. More recently, several reports indicate the importance of these metabolic changes for tumorigenesis highlighting the likelihood that inhibition of these activities could prevent cancer associated disease.

Global Measurement of Metabolic Activity: Liquid Chromatography-Mass Spectrometry
In order to elucidate pathogenic manipulation of the metabolic network (either viral or cancer-associated), we utilize liquid chromatography/ tandem mass spectrometry (LC-MS/MS) to measure the concentrations of specific metabolite pools. Utilizing this technology, we can measure the concentrations of a wide variety of metabolites, covering a large proportion of metabolic chemical diversity.

In addition to measuring metabolite concentrations, we also measure the rate of molecular conversion from one metabolite to another, i.e. metabolic flux. The speed of metabolic flux is crucial to understanding metabolic network behavior and how it is affected by a cellular perturbation, e.g. viral infection or oncogenic transformation. We measure metabolic flux by feeding cells with stable-isotope-labeled nutrient, e.g. 13C-glucose, which because of its heavier composition (as compared to 12C) produces a unique mass signature. As 13C incorporates into the metabolic network it can be distinguished from 12C-metabolites by mass spectrometry. By measuring the speed of 13C incorporation into various metabolite pools we can estimate metabolic flux values and how they are affected by various perturbations.

With respect to our HCMV project, we have found that HCMV infection activates several metabolic pathways including various aspects of central carbon metabolism and nucleotide biosynthesis. We find that inhibition of certain virally-up-regulated pathways blocks normal viral replication. In our cancer project, we have begun to identify activities specifically induced by oncogenesis that appear to be important for cancer-cell replication. Utilizing molecular genetic techniques, we are now beginning to dissect the mechanisms responsible for viral and cancer-induced metabolic changes. Increased understanding of these mechanisms and the roles they play during viral infection and cancer-cell transformation will continue to illuminate potential therapeutic avenues.

 
 Selected Publications
List All   |   Timeline
  1. Mathers C, Spencer CM, Munger J. Distinct Domains within the Human Cytomegalovirus UL26 Protein Are Important for Wildtype Viral Replication and Virion Stability. PLoS One. 2014; 9(2):e88101.
    View in: PubMed
  2. Ortiz-Riaño E, Ngo N, Devito S, Eggink D, Munger J, Shaw ML, de la Torre JC, Martínez-Sobrido L. Inhibition of arenavirus by a3, a pyrimidine biosynthesis inhibitor. J Virol. 2014 Jan; 88(2):878-89.
    View in: PubMed
  3. Pei S, Minhajuddin M, Callahan KP, Balys M, Ashton JM, Neering SJ, Lagadinou ED, Corbett C, Ye H, Liesveld JL, O'Dwyer KM, Li Z, Shi L, Greninger P, Settleman J, Benes C, Hagen FK, Munger J, Crooks PA, Becker MW, Jordan CT. Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells. J Biol Chem. 2013 Nov 22; 288(47):33542-58.
    View in: PubMed
  4. Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brüstle A, Harris IS, Holmes R, Wakeham A, Haight J, You-Ten A, Li WY, Schalm S, Su SM, Virtanen C, Reifenberger G, Ohashi PS, Barber DL, Figueroa ME, Melnick A, Zúñiga-Pflücker JC, Mak TW. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012 Aug 30; 488(7413):656-9.
    View in: PubMed
  5. McArdle J, Moorman NJ, Munger J. HCMV targets the metabolic stress response through activation of AMPK whose activity is important for viral replication. PLoS Pathog. 2012 Jan; 8(1):e1002502.
    View in: PubMed
  6. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011 Dec 23; 35(6):871-82.
    View in: PubMed
  7. Hollenbaugh JA, Munger J, Kim B. Metabolite profiles of human immunodeficiency virus infected CD4+ T cells and macrophages using LC-MS/MS analysis. Virology. 2011 Jul 5; 415(2):153-9.
    View in: PubMed
  8. Spencer CM, Schafer XL, Moorman NJ, Munger J. Human cytomegalovirus induces the activity and expression of acetyl-coenzyme A carboxylase, a fatty acid biosynthetic enzyme whose inhibition attenuates viral replication. J Virol. 2011 Jun; 85(12):5814-24.
    View in: PubMed
  9. McArdle J, Schafer XL, Munger J. Inhibition of calmodulin-dependent kinase kinase blocks human cytomegalovirus-induced glycolytic activation and severely attenuates production of viral progeny. J Virol. 2011 Jan; 85(2):705-14.
    View in: PubMed
  10. Munger J, Bennett BD, Parikh A, Feng XJ, McArdle J, Rabitz HA, Shenk T, Rabinowitz JD. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat Biotechnol. 2008 Oct; 26(10):1179-86.
    View in: PubMed
  11. Munger J, Bajad SU, Coller HA, Shenk T, Rabinowitz JD. Dynamics of the cellular metabolome during human cytomegalovirus infection. PLoS Pathog. 2006 Dec; 2(12):e132.
    View in: PubMed
  12. Munger J, Yu D, Shenk T. UL26-deficient human cytomegalovirus produces virions with hypophosphorylated pp28 tegument protein that is unstable within newly infected cells. J Virol. 2006 Apr; 80(7):3541-8.
    View in: PubMed
  13. Benetti L, Munger J, Roizman B. The herpes simplex virus 1 US3 protein kinase blocks caspase-dependent double cleavage and activation of the proapoptotic protein BAD. J Virol. 2003 Jun; 77(11):6567-73.
    View in: PubMed
  14. Munger J, Hagglund R, Roizman B. Infected cell protein No. 22 is subject to proteolytic cleavage by caspases activated by a mutant that induces apoptosis. Virology. 2003 Jan 20; 305(2):364-70.
    View in: PubMed
  15. Hagglund R, Munger J, Poon AP, Roizman B. U(S)3 protein kinase of herpes simplex virus 1 blocks caspase 3 activation induced by the products of U(S)1.5 and U(L)13 genes and modulates expression of transduced U(S)1.5 open reading frame in a cell type-specific manner. J Virol. 2002 Jan; 76(2):743-54.
    View in: PubMed
  16. Munger J, Roizman B. The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc Natl Acad Sci U S A. 2001 Aug 28; 98(18):10410-5.
    View in: PubMed
  17. Munger J, Chee AV, Roizman B. The U(S)3 protein kinase blocks apoptosis induced by the d120 mutant of herpes simplex virus 1 at a premitochondrial stage. J Virol. 2001 Jun; 75(12):5491-7.
    View in: PubMed
  18. Galvan V, Brandimarti R, Munger J, Roizman B. Bcl-2 blocks a caspase-dependent pathway of apoptosis activated by herpes simplex virus 1 infection in HEp-2 cells. J Virol. 2000 Feb; 74(4):1931-8.
    View in: PubMed

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