Dr. Dusanka Skundric |
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Wayne State University School of Medicine Neurology Neuroimmunology Assistant Professor Wayne State University Medicine Internal Medicine Endocrinology Assistant Professor Wayne State University School of Medicine Immunology and Microbiology Assistant Professor |  |
Mailing Address421E Canfield 2226 Elliman Building Detroit, Michigan 48201United States | Contact Information |
Qualifications
M.D., University of Belgrade.
Ph.D., University of Belgrade, Immunology.
Expertise and Research Interests
The overall objective of my research is to understand molecular basis of T-cell and cytokine mediated mechanisms involved in injury of glia and neurons in immune-mediated neurological diseases. Such studies are expected to ultimately foster our efforts in development of new, more specific therapies to prevent, ameliorate or repair damage of neuronal tissue.
My laboratory studies immune regulation of autoimmune diseases of the central (CNS) and peripheral (PNS) nervous systems. In the area of CNS autoimmune diseases, we are investigating molecular and immune mechanisms that regulate relapsing experimental autoimmune encephalomyelitis (EAE). EAE is commonly used as an experimental model for human demyelinating disease, multiple sclerosis (MS). We have described a novel model of relapsing-remitting EAE in response to H-2b restricted encephalotogenic epitope ofmyelin ologodendrocyte protein (MOG 35-55) in (B6 x SJL) F1 (H-2 b/s) mice. We utilize this EAE model to study immune regulation of MOG35-55 specific T cell homing, immunomoduation of CD4+Th1 effector functions, and interactions between immune and glial cells.
We identified an important role of a cytokine IL-16, in regulation of relapsing EAE and potentially MS. We observed profound similarities in regulation of IL-16 production by T-cells, between the newly described EAE model and MS lesions. Our data suggest importance of IL-16 mediated mechanisms in regulation of inflammation and changes of axonal cytoskeleton. In MS lesions, we found that production of bioactive IL-16 corresponded to levels of phosphorylated medium and heavy chains of neurofilament, which are often typical signs of early inflammation-mediated axonal damage Our results further suggest engagement of active-caspase-3 dependent mechanism in local IL-16 production, in EAE and MS. In mouse EAE, we showed that specific neutralization of IL-16 leads to marked reduction of severity and frequency of relapse. Such therapy markedly reduced demyelination and axonal damage, and improved gain of motor function during remissions. Beneficial results achieved by anti-IL-16 therapy were mainly due to reduction of CD4+ T cell infiltration. Subsequently, in MS lesions, we showed that regulation of IL-16 correlated with infiltration by CD4+T-bet+ STAT-1+ Th1 cells.
IL-16 is a specific chemoattractant factor for CD4+ cells. It is involved in regulation of CD4+ T cell specific trafficking in allergy and some autoimmune diseases. Neuronal form of IL-16 has been recently identified, and its function in neuronal homeostasis and/or pathology remains to be investigated. Our ongoing studies of molecular mechanisms of IL-16 regulation and specific signaling in T-cells have broader relevance to potentially similar regulatory mechanisms associated with neuronal function.
In the area of PNS, we are focused on studying the role of neuropoietic cytokines in Schwann cell (SC) - axonal communication and in degeneration of the peripheral nerve.
To study cytokine mediated mechanisms in diabetic neuropathy, we used an inbred spontaneously diabetic rat strain, which develops microvascular and neurological complications similar to humans. The initial gene array analysis of peripheral nerves from diabetes-prone (BBW/DP), and congenic diabetes-resistant rats (BBW/DR), revealed existing similarities in patterns of regulation between families of genes of interest, throughout the course of diabetic neuropathy. We extended on this initial observation, and confirmed gene array data by in situ analysis and in vitro experiments. We found that neuropoietic cytokine IL-6, has an important role in regulation of Na+ channel beta-3 subunit expression. While hyperglycemia suppresses the expression of beta-3 subunit of Na+ gated voltage channel, addition of IL-6 to SC cultures, can successfully prevent or reverse effects of hyperglycemia on beta-3 expression. This data has direct relevance for therapy of diabetic neuropathy, and suggests neuroprotective role of IL-6. We also provided evidence suggesting activation of IL-1 signaling pathway during diabetic neuropathy. Similarly to IL-1, we found elevation of TNFα production, which paralleled with upregulation of caspases-3, 6, 7 and 9, and suggested association of this cytokine with SC apoptosis in diabetic nerves.
My laboratory studies immune regulation of autoimmune diseases of the central (CNS) and peripheral (PNS) nervous systems. In the area of CNS autoimmune diseases, we are investigating molecular and immune mechanisms that regulate relapsing experimental autoimmune encephalomyelitis (EAE). EAE is commonly used as an experimental model for human demyelinating disease, multiple sclerosis (MS). We have described a novel model of relapsing-remitting EAE in response to H-2b restricted encephalotogenic epitope ofmyelin ologodendrocyte protein (MOG 35-55) in (B6 x SJL) F1 (H-2 b/s) mice. We utilize this EAE model to study immune regulation of MOG35-55 specific T cell homing, immunomoduation of CD4+Th1 effector functions, and interactions between immune and glial cells.
We identified an important role of a cytokine IL-16, in regulation of relapsing EAE and potentially MS. We observed profound similarities in regulation of IL-16 production by T-cells, between the newly described EAE model and MS lesions. Our data suggest importance of IL-16 mediated mechanisms in regulation of inflammation and changes of axonal cytoskeleton. In MS lesions, we found that production of bioactive IL-16 corresponded to levels of phosphorylated medium and heavy chains of neurofilament, which are often typical signs of early inflammation-mediated axonal damage Our results further suggest engagement of active-caspase-3 dependent mechanism in local IL-16 production, in EAE and MS. In mouse EAE, we showed that specific neutralization of IL-16 leads to marked reduction of severity and frequency of relapse. Such therapy markedly reduced demyelination and axonal damage, and improved gain of motor function during remissions. Beneficial results achieved by anti-IL-16 therapy were mainly due to reduction of CD4+ T cell infiltration. Subsequently, in MS lesions, we showed that regulation of IL-16 correlated with infiltration by CD4+T-bet+ STAT-1+ Th1 cells.
IL-16 is a specific chemoattractant factor for CD4+ cells. It is involved in regulation of CD4+ T cell specific trafficking in allergy and some autoimmune diseases. Neuronal form of IL-16 has been recently identified, and its function in neuronal homeostasis and/or pathology remains to be investigated. Our ongoing studies of molecular mechanisms of IL-16 regulation and specific signaling in T-cells have broader relevance to potentially similar regulatory mechanisms associated with neuronal function.
In the area of PNS, we are focused on studying the role of neuropoietic cytokines in Schwann cell (SC) - axonal communication and in degeneration of the peripheral nerve.
To study cytokine mediated mechanisms in diabetic neuropathy, we used an inbred spontaneously diabetic rat strain, which develops microvascular and neurological complications similar to humans. The initial gene array analysis of peripheral nerves from diabetes-prone (BBW/DP), and congenic diabetes-resistant rats (BBW/DR), revealed existing similarities in patterns of regulation between families of genes of interest, throughout the course of diabetic neuropathy. We extended on this initial observation, and confirmed gene array data by in situ analysis and in vitro experiments. We found that neuropoietic cytokine IL-6, has an important role in regulation of Na+ channel beta-3 subunit expression. While hyperglycemia suppresses the expression of beta-3 subunit of Na+ gated voltage channel, addition of IL-6 to SC cultures, can successfully prevent or reverse effects of hyperglycemia on beta-3 expression. This data has direct relevance for therapy of diabetic neuropathy, and suggests neuroprotective role of IL-6. We also provided evidence suggesting activation of IL-1 signaling pathway during diabetic neuropathy. Similarly to IL-1, we found elevation of TNFα production, which paralleled with upregulation of caspases-3, 6, 7 and 9, and suggested association of this cytokine with SC apoptosis in diabetic nerves.
Future Research
Our accomplishments have provided a solid base to further extend our search of new molecular pathways, which regulate neuroinflammation, demyelination and axonal deficiency in multiple sclerosis. In our future work we will continue to broaden our understanding of autoimmune processes, and besides diseases of central nervous system (CNS), our studies will include some other CD4+Th1-mediated organ specific autoimmune diseases, such as type 1 diabetes mellitus (T1DM). Our overall goal in finding the cure for autoimmune induced inflammation, subsequent target tissue damage and remote complications, will remain. In our future research we plan to continue with multifaceted analyses of experimental and human tissues. We will retain in vivo studies utilizing originally developed model of relapsing-remitting MOG-induced EAE in (B6 x SJL) F1 mice in combination with other transgenic lines, which are either already available or will be specifically developed by our laboratory. We will further extend in vitro analysis of molecular pathways relevant for T cell, glia and neuronal interactions. Our translational approach will be taken further to analyzing human tissue and samples from patients suffering from autoimmune diseases. Hopefully, this full circle, will prove to be translational leading us from bench to bedside and enabling development of new therapies, which alone or in combination with other therapies will be used to cure autoimmune inflammation and tissue destruction.
Industrial Relevance
Our research has direct relevance for developing new therapies to prevent and ameliorate or halt the progression of autoimmune diseases, such as multiple sclerosis (MS) and type 1 diabetes mellitus (T1DM) and their complications. Our research has potentially broader relevance for developing new therapies to abrogate diminish inflammation, promote remyelination and enhance neuronal regeneration.
Keywords
COS Keywords:
Autoimmunity, Diabetes, Immunology, Microbiology, Molecular Biology, Neuroimmunology, Neurology, Pathophysiology.Additional Terms:
Cytokines, Glia-neuronal Interactions, Immune Cell-cell Interaction, Inflammation, T Cell Trafficking.Languages
(Reading, Writing, Speaking)
English: (Fluent, Fluent, Fluent)
Serbian: (Fluent, Fluent, Fluent)
Latin: (Functional, Functional, Functional)
French: (Basic, Basic, Basic)
Italian: (Basic, Basic, Basic)
Memberships
American Association of Immunologists
American Diabetes Association
Immunology of Diabetes Society
Neuroimmunology Society
New York Academy of Sciences
Serbian Medical Association
Society for Mucosal Immunology
Honors and Awards
Visiting Research Fellow,
Republic Science Foundation of Serbia,
Department of Immunology, Rayne Institute, St. Thomas's Hosp., London,
Immunology
Visiting Research Fellow,
British Council,
Department of Physiology,St. Thomas's Hospital, London, England,
Neuroimmunology
Fogarty International Fellow,
Department of Neuropathology, Albert Einstein College of Medicine, Bronx, NY ,
Neuroimmunology
Javits Fellow,
NIH,
Department of Neurology, Wayne State University, Detroit, MI,
Neuroimmunology
Career Development Award,
American Diabetes Association,
Department of Neurology, Wayne State University,
Neuroimmunology
Junior Faculty Travel Award,
American Association of Immunologists (AAI)
Travel Award,
Federation of Clinaical Immunology Societies (FOCIS)
Previous Positions
Javits Fellow,
Wayne State University,
Medicine,
Neurology,
Neuroimmunology
Assistant Professor,
University of Belgrade,
Medicine,
Pathophysiology
Associate Professor,
University of Belgrade,
Medicine,
Pathophysiology
Fogarty International Fellow,
Albert Einstein College of Medicine,
Medicine,
Neuropathology,
Neuroimmunology
Funding Received
- National Multiple Sclerosis Society (NMSS): Protection of oligodendrocytes by cyclic GMP and metabotropic glutamate receptors, Skundri DS - Co-Inve, 2005 to 2008.
- National Multiple Sclerosis Society (NMSS): Molecular mechanisms of oligodendrocyte damage by MOG35-55 specific T cells, Skundric DS - PI, 2003 to 2004.
- National Multiple Sclerosis Society (NMSS): Role of MCP-1 in Relapsing Form of EAE, Skundric DS - PI, 2000 to 2001.
- American Diabetes Association (ADA): Career Development Award - Modulation of Schwann Cell-Axonal Communication by Cytokines in Diabetic Neuropathy, Skundric DS - PI, 1999 to 2003.
Publications
- Dusanka S. Skundric, Rujuan Dai, Vaagn L.Zakarian, Weili Zhou (2008) Autoimmune-induced preferential depletion of myelin-associated glycoprotein (MAG) is genetically regulated in relapsing EAE (B6 x SJL) F1 mice, Mol Neurodegener, 3 (1), 7
- Skundric DS, Cai J, Cruikshank WW, Gveric D (2006) Production of IL-16 Correlates with CD4+ Th1 Inflammation and Phosphorylation of Axonal Cytoskeleton in Multiple Sclerosis (MS) Lesions, Journal of Neuroinflammation, http://www.jneuroinflammation.com/content/3/1/13
- Lisak RP, Benjamins JA, Yao B, Land S, Nedekoska L, Skundric DS (2006) Differential Effects of Th1, Monocyte/Macrophage and Th2 Cytokine Mixtures on Early Gene Expression for Immune Related Molecules by Central Nervous System Mixed Glial Cell Cultures, Multiple Sclerosis, 12, 149-168
- Skundric, DS, Zhou, W, Cruikshank, WW, Dai, R (2005) Increased Levels of Bioactive IL-16 Correlate With Disease Activity During Relapsing Experimental Autoimmune Encephalomyelitis (EAE), Journal of Autoimmunity, 25 (3), 205-214
- Skundric DS, Dai R, Zakarian VL, Bessert D, Skoff RP, Cruikshank WW, Kurjakovic Z, Anti-IL-16 Therapy Reduces CD4+ T-cell Infiltration and Improves Paralysis
and Histopathology of Relapsing EAE., Journal of Neuroscience Research, 79(5), 680-93, Mar 2005
- Dusanka S. Skundric, Experimental Models of Relapsing-Remitting Multiple Sclerosis: Current Concepts and Perspectives (review), Current Neurovascular Research, 2(4), 349-362, 2005
- Dusanka S. Skundric, Rujuan Dai, Philip Mataverde (2003) IL-6 Modulates Hyperglycemia-Induced Changes of Na Channel Beta-3 Subunit Expression by Schwann Cells, Annals of the New York Academy of Sciences, 1005, 233-236
- Skundric DS, Zakarian V, Dai R, Lisak RP, Tse HY, James J, Distinct immune regulation of the response to H-2b restricted epitope of
MOG causes relapsing-remitting EAE in H-2b/s mice, Journal of Neuroimmunology, 136(1-2), 34-45, March 2003
- Dusanka S. Skundric, Robert P. Lisak, Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration (review), Experimental Diabesity Research, 4(4), 303-12, 2003
- Skundric DS, Dai R, James J, Lisak RP, Activation of IL-1 signaling pathway in Schwann cells during diabetic
neuropathy, Annals of the New York Academy of Sciences, 958, 393-8, April 2002
- Skundric DS, Lisak RP, Rouhi M, Kieseier BC, Jung S, Hartung HP, Schwann cell-specific regulation of IL-1 and IL-1Ra during EAN: possible
relevance for immune regulation at paranodal regions, Journal of Neuroimmunology, 116(1), 74-82, May 2001
- Milic V, Skundric DS (2000) Prilog Klasifikaciji Hereditarnih Neuropatija, Klinicka I Experimentalna Neurologija, 5 (7), 399-404
- Skundric DS, Bealmear B, Lisak RP, Induced upregulation of IL-1, IL-1RA and IL-1R type I gene expression by
Schwann cells, Journal of Neuroimmunology, 74(1-2), 9-18, April 1997
- Lisak RP, Skundric DS, Belmear B, Ragheb S (1997) The role of cytokines in Schwann cell damage, protection and repair, Journal of Infectious Disease, 176 (Suppl 2), 173-179
- Skundric DS, Huston K, Shaw M, Tse HY, Raine CS, Experimental allergic encephalomyelitis. T cell trafficking to the central
nervous system in a resistant Thy-1 congenic mouse
strain, Laboratory Investigation; a Journal of Technical Methods and Pathology, 71(5), 671-9, November 1994
- Skundric DS, Kim C, Tse HY, Raine CS, Homing of T cells to the central nervous system throughout the course of
relapsing experimental autoimmune encephalomyelitis in Thy-1 congenic
mice, Journal of Neuroimmunology, 46(1-2), 113-21, July 1993
- Skundric DS, Zlokovic BV, Rakic L, Dawson H (1992) Role of the blood-brain barrier in immunopathogenesis of experimentally induced autoimmune demyelination In Segal MB (eds), Barriers and fluids of the eye and brain, London, MacMillan Press, 210-212 pages (bookchapter)
- Zlokovic BV, Skundric DS, Segal MB, Lipovac MN, Mackic JB, Davson H, A saturable mechanism for transport of immunoglobulin G across the
blood-brain barrier of the guinea pig, Experimental Neurology, 107(3), 263-70, March 1990
- Skundric DS, Zlokovic BV, Lackovic V (1990) Immunohistochemical study of blood-brain barrier permeability to blood-born IgG during allergic encephalomyelitis in the guinea pig, Giornale di Malattie Infettive e Parasitarie, 42 (8), 729-731
- Zlokovic BV, Skundric DS, Segal MB, Colover J, Jankov RM, Pejnovic N, Lackovic V, Mackic J, Lipovac MN, Davson H, Et Al., Blood-brain barrier permeability changes during acute allergic, Metabolic Brain Disease, 4(1), 33-40, March 1989
- Colover J, Skundric DS (1989) Chain of events leading to demyelination In Gonsette RE, Delmotte P (eds), Recent advances in multiple sclerosis therapy, Elsevier Science Publishers, 305-308 pages (bookchapter)
Profile Details
Last Updated: 6/15/2008
COS Expertise ID #994710
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