There are approximately 250 neurological " brain and nervous system " disorders. Combined, neurologic disorders are the leading cause of death, disability and loss of quality of life worldwide according to the World Health Organization. The incidence of these disorders ranges from stroke, epilepsy and Alzheimer's, which affect millions, to rare diseases such as amyotrophic lateral sclerosis and ataxia's. To address the problem of brain and nervous system disorders investigators have focused attention on describing cell injury mechanisms. However, discovery of cell survival strategies could have profound impact on the treatment of neurologic disorders and disease and is an area that has not yet been rigorously investigated. Recently we developed a strategy to discover neuroprotective genes from preconditioned neural tissue. Some of these genes provide protection not only against ischemic and excitotoxic injury but are also protective against apoptosis and serum withdrawal. This is very exciting, suggesting that it might be possible to find molecules that are broadly protective and therefore might provide new treatment strategies. From this screen we identified a gene, Thorase, encoding a protein of unknown function that is potently neuroprotective that and proposed the following aims to explore the biologic function of Thorase.
Aim 1 : What is the anatomical and cellular localization of Thorase? Aim 2: What is the biologic function of Thorase? New Aim Aim 3: What is the role of Thorase in Neuroprotection? Aim 4: Is Thorase neuroprotective in vivo? On completion of these studies we will have identified the biologic actions of Thorase and the survival pathways it mediates, as well as, identified potential disease targets that might benefit from expression of Thorase. Our long-term goal is to understand the function of Thorase so that translational therapy can be developed.

Public Health Relevance

. Combined, neurologic disorders are the leading cause of death, disability and loss of quality of life worldwide according to the World Health Organization. Preconditioning amplifies the human body's natural host defense system to provide profound and broad protection. Understanding the preconditioning signal cascade has tremendous potential to develop pharmaceutical treatments of patients at risk for ischemic injury and perhaps for treating chronic neurodegenerative diseases. This project seeks to understand how a newly discovered protein in preconditioning protects the brain in order to develop new therapeutic treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029368-05
Application #
8289522
Study Section
Special Emphasis Panel (ZRG1-CDIN-T (03))
Program Officer
Wise, Bradley C
Project Start
2008-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$318,754
Indirect Cost
$124,392
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Chen, Yu-Chan; Umanah, George K E; Dephoure, Noah et al. (2014) Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins. EMBO J 33:1548-64
Zhang, Jianmin; Wang, Yue; Chi, Zhikai et al. (2011) The AAA+ ATPase Thorase regulates AMPA receptor-dependent synaptic plasticity and behavior. Cell 145:284-99