We hypothesize that the anti-inflammatory cytokines IL-13 and IL-4 play an important role in the death of dopaminergic neurons in the Substantia nigra pars compacta (SNc), the same cells that are lost in human Parkinson's disease (PD). This hypothesis is based on our preliminary studies in mice which showed that interleukin 13 receptor alpha 1 chain (IL-13R?1), is highly expressed in DA neurons in the SNc and that mice that are deficient is this receptor are protected from the loss of dopaminergic (DA) neurons that occurs during chronic peripheral injection with low doses of LPS. Furthermore, in vitro studies using a dopaminergic cell line showed that while IL-13 alone does not have harmful effects on DA neurons, it strongly potentiates the toxicity of mild oxidative stress. Similar results were obtained with IL-4, another cytokine capable of activating IL- 13R?1-dependent signaling. Together these results suggest a novel mechanism whereby anti-inflammatory cytokines can contribute to neuronal loss under conditions of stress. We propose to investigate our hypothesis in three specific aims. In SA1, we will determine how the interaction between IL-13 (and IL-4) signaling and oxidative stress induces neuronal damage in vitro. In SA2, we will investigate the contribution of each of these cytokines to neuronal loss in vivo in a model of neuro-inflammation. In SA3, we will determine the cellular source of IL-13 and IL-4 during inflammation. These studies are highly relevant to understanding the role of inflammation in the pathogenesis of PD and may identify novel therapeutic targets for the treatment of this disease.

Public Health Relevance

We propose to investigate the role of two cytokine signaling molecules, interleukins 13 and 4, in the survival of dopaminergic neurons in the brain during neuro-inflammation. The results are highly relevant to understanding the pathophysiology of Parkinson's Disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS085155-01
Application #
8612661
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sieber, Beth-Anne
Project Start
2013-09-01
Project End
2018-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$440,056
Indirect Cost
$155,506
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037