Date of Award

1-1-2009

Embargo Period

2-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Naren L. Banik

Second Advisor

James A. Cook

Third Advisor

Gary S. Gilkeson

Fourth Advisor

Edward L. Hogan

Fifth Advisor

Baerbel Rohrer

Sixth Advisor

William R. Tyor

Abstract

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS) that affects approximately 400,000 people in the United States every year and results in fatigue, visual dysfunction, and paralysis. Inflammatory events associated with MS include activation of auto-reactive T cells and migration of these and other immune cells into the CNS, leading to production of cytokines and other mediators and to demyelination. Astrogliosis and microgliosis are also prominent inflammatory features of MS. Neurodegenerative events such as axonal damage and loss of neurons and oligodendrocytes also contribute to clinical disease symptoms. Cell death is thought to occur, at least partially, through induction of multiple pathways leading to apoptosis. Current therapies for MS are immunomodulary; however, therapies that inhibit both inflammatory and neurodegenerative events may be more beneficial in reducing clinical disease symptoms. One such target is the calcium-mediated neutral protease calpain. Calpain is involved in many normal physiological events, but when calpain activity is uncontrolled, can lead to many of the above mentioned pathophysiological changes that are associated with neurodegenerative diseases such as MS. Since calpain expression and activity are upregulated in immune cells and CNS tissue from MS patients and from animals with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we hypothesized that increased calpain expression and activity correlated with both inflammatory and neurodegenerative changes in spinal cord from EAE animals. A corollary hypothesis is that calpain inhibitor therapy would reduce disease severity by attenuating these pathophysiological events. Three specific aims were designed to test these hypotheses. First, the timing of calpain upregulation in spinal cord was characterized in an acute Lewis rat model in order to identify an appropriate timing regimen for calpain inhibitor therapy. Next, the effects of daily calpain inhibitor treatment in acute EAE animals were examined. Finally, the effects of specifically blocking calpain activity in auto-reactive T cells before adoptive transfer to induce a more clinically relevant, relapsing EAE model were tested. The data obtained from these experiments indicated that calpain inhibition did reduce disease severity by attenuating multiple pathophysiological events; thus suggesting that calpain is a viable target for treating MS.

Rights

All rights reserved. All rights reserved. Copyright is held by the author.

Download

Share

COinS