Excess ion channel activation can have devastating consequences for the nervous system, often resulting in cell death. Excitotoxic or ion-channel mediated cell death is a major cause of the debilitating loss of neurons that occurs during pathological conditions such as ischemic stroke1, and is also a contributing factor in a variety of human neurodegenerative diseases including amyotrophic lateral sclerosis (ALS)2. Preliminary work on a Caenorhabditis elegans model of excitotoxicity shows that in cases where cell body death is prevented, axonal destabilization still occurs3. The goal of this proposal is to identify the mechanisms underlying synaptic decoupling and altered calcium homeostasis in axons, which occur during excitotoxic cell damage.
In Aim 1, I will test the hypothesis that axonal destabilization is mediated through increased calcium stores and requires both voltage gated and ER localized channel receptors.
In Aim 2, I will identify the role of calcium in axon destabilization and implicate specific classes of calcium channels in mediating the accumulation of toxic levels of calcium in axons.

Public Health Relevance

Excitotoxicity occurs as a result of many prevalent human pathologies, such as stroke and amyotrophic later sclerosis (ALS). The work proposed will identify the mechanisms that are responsible for mediating excitotoxic cell death. The mechanisms of cell death in axons can be used as targets for the treatment and prevention of axon loss in neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS076326-03
Application #
8512827
Study Section
Special Emphasis Panel (ZRG1-F03A-F (20))
Program Officer
Gubitz, Amelie
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$28,746
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655