Strong evidence suggests that multiple sclerosis (MS) is mediated through an autoimmune attack by myelin-specific T cells causing damage to myelinated axons and cells. Understanding the underlying mechanisms by which T cells become activated, migrate into CMS,and exert damage is crucial to treating the demyelinating disease. Calpain, a calcium (Ca )-activated neutral protease, has been implicated in MS. This competing renewal application will determine whether alterations in calpain activity in relapse and remission MS patients are involved in T cell activation and migration, Th1/Th2 dysregulation, epitope spreading, and/or axonal damage and neuronal and glial cell death and, thus, examine the effects of calpain inhibition on these events. Preliminary data suggest that calpain expression and activity, concomitant with increased interieukin (IL)-2 production (Th1), are upregulated in MS plasma and peripheral blood mononuclear cells (PBMCs) supernatant of MS patients, compared to controls. The increase in IL-2 production in relapse and remission groups correlated with increased translocation of the nuclear factor NFATd. In contrast, IL-4 and IL-10 (Th2) levels were highest in MS remission compared to relapse. Calpain released from MS patient cells degraded MBP and calpain's activity was increased in primary astrocytes and microglia treated with interferon (IFN)-y (increased in MS). We hypothesize that increased calpain expression and activity in MS PBMCs and MBP-specific T cells in relapse and remission patients will correlate with changes in Th1/Th2 cytokine profiles, NFAT translocation, and IL-2 production;and that released calpain and other inflammatory factors from activated T cells will damage axons and neurons and degrade MBP into antigenic peptides. Calpain inhibitor treatment will inhibit T cells activation and migration, reduce pro-inflammatory response, and attenuate cell death and axon damage. These hypotheses will be tested by the following specific aims: (1) examine the correlation between calpain expression and activity and levels of Th1/Th2 cytokines in MS PBMCs and MBP-specific T cells, and plasma, compared to controls;(2) determine the mechanisms of activation and migration of MS PBMCs and MBP-specific T cells and examine the effects of calpain inhibition;determine whether MBP digestion into immunogenic peptides is calpain-dependent and if the peptides sufficiently activate MS T cells;(3) examine whether supematants from activated MBP-specific T cells and PBMCs cause damage and/or death to primary cortical neurons and oligodendrocytes (human), and primary rat oligodendrocytes in culture and whether calpain inhibitors provide neuron protection and restore function. Understanding the mechanisms may help develop therapeutic strategies (e.g., calpain as a target) for treatment of MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041088-09
Application #
7590468
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Utz, Ursula
Project Start
2001-01-15
Project End
2012-02-29
Budget Start
2009-03-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2009
Total Cost
$318,974
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Trager, Nicole N M; Butler, Jonathan T; Harmon, Jennifer et al. (2018) A Novel Aza-MBP Altered Peptide Ligand for the Treatment of Experimental Autoimmune Encephalomyelitis. Mol Neurobiol 55:267-275
Smith, Amena W; Rohrer, Baerbel; Wheless, Lee et al. (2016) Calpain inhibition reduces structural and functional impairment of retinal ganglion cells in experimental optic neuritis. J Neurochem 139:270-284
Podbielska, Maria; Das, Arabinda; Smith, Amena W et al. (2016) Neuron-microglia interaction induced bi-directional cytotoxicity associated with calpain activation. J Neurochem 139:440-455
Lee, Philip; Murphy, Ben; Miller, Rickey et al. (2015) Mechanisms and clinical significance of histone deacetylase inhibitors: epigenetic glioblastoma therapy. Anticancer Res 35:615-25
Das, Arabinda; Miller, Rickey; Lee, Philip et al. (2015) A novel component from citrus, ginger, and mushroom family exhibits antitumor activity on human meningioma cells through suppressing the Wnt/?-catenin signaling pathway. Tumour Biol 36:7027-34
Agrawal, Neena Stephanie; Miller Jr, Rickey; Lal, Richa et al. (2014) Current Studies of Immunotherapy on Glioblastoma. J Neurol Neurosurg 1:
Park, Sookyoung; Nozaki, Kenkichi; Smith, Joshua A et al. (2014) Cross-talk between IGF-1 and estrogen receptors attenuates intracellular changes in ventral spinal cord 4.1 motoneuron cells because of interferon-gamma exposure. J Neurochem 128:904-18
Miller Jr, Rickey; DeCandio, Michele L; Dixon-Mah, Yaenette et al. (2014) Molecular Targets and Treatment of Meningioma. J Neurol Neurosurg 1:
Trager, Nicole; Smith, Amena; Wallace Iv, Gerald et al. (2014) Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis. J Neurochem 130:268-79
Varma, Abhay K; Das, Arabinda; Wallace 4th, Gerald et al. (2013) Spinal cord injury: a review of current therapy, future treatments, and basic science frontiers. Neurochem Res 38:895-905

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