Axonal degeneration is the major cause irreversible neurological disability patients multiple of in with sclerosis (MS). Previous examination of postmortem MS brains and spinal cords has identified three settings of axonal and neuronal degeneration. 1) Axons are transected during inflammatory demyelination. 2) Demyelination of the cerebral cortex transects axons and dendrites and causes neuronal apoptosis. 3) Chronically demyelinated axons degenerate. The overall goal of this project is to extend our previous studies by gaining insight, into the molecular mechanisms responsible for degeneration of chronically demyelinated axons. Such knowledge is essential for the development of neuroprotective therapeutics that will stop or delay the relentless progression of neurological disability in MS patients. Our studies are based upon the hypothesis that alterations in the molecular composition of the axolemma and reduced mitochrondrial function initiate a vicious cycle of axonal changes that cannot be controlled by the neuron or chronically demyelinated axon. Reduced energy inhibits axonal transport and mitochrondrial renewal which further decreases energy production. The increased energy demands of nerve conduction through demyelinated axons cannot be met resulting in a series of ionic imbalances that increases axonal calcium and destroys the axon. Our studies are divided into two Specific Aims. The first will continue to examine postmortem MS brains and spinal cords by characterizing the composition and distribution of proteins in the chemically demyelinated axon, determining the distribution and functional status of axonal mitochrondria and by characterizing axonal organelles that reflect or contribute to altered axon transport and to axonal degeneration.
The second aim i s designed to directly test various aspects of our hypothesis in an animal model of chronic axonal degeneration. Collectively, these studies should identify therapeutic targets that could stop or delay neurodegeneration in MS patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS038667-08
Application #
7350243
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
8
Fiscal Year
2007
Total Cost
$291,810
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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