A common feature of neurodegenerative diseases is the aberrant and excessive loss of neurons by activation of apoptosis. Numerous molecules involved in the promotion or inhibition of neuronal apoptosis have been identified and these are being organized as components of signal transduction pathways. This proposal focuses on histone deacetylases (HDACs), a family of enzymes originally identified on the basis of their ability to deacetylate histones. More recent work has shown that HDACs are involved in a variety of different biological processes and they have therefore emerged as the subject of intense investigation. We have found that one member of the HDAC family of proteins, HDAC4, protects neurons from apoptosis. Neuroprotection does not involve signaling pathways that are commonly used by other survival-promoting genes and biological factors. The objective of the proposal is to use a multi-pronged approach to elucidate the mechanism by which HDAC4 exerts its neuroprotective action with the long-term goal of developing novel and effective strategies to prevent cell death in neurodegenerative pathologies.
The specific aims are- (1) To identify the region within HDAC4 that mediates neuroprotection, (2) To identify HDAC4-interacting proteins in neurons using mass-spectrometry, and (3) To identify downstream targets of HDAC4 action in neurons with a focus on cell cycle components. ?

Public Health Relevance

Neurological diseases disrupt the quality of life for patients and cost society billions of dollars annually. While symptomatic treatments are available for many neurological diseases, a cure is not presently available. Identifying molecules that regulate neuronal survival and understanding the mechanism by which they act would lead to the development of more effective therapeutic strategies. Our proposal focuses on HDAC4, a protein that is neuroprotective. It is our hope that the results from the studies we propose will shed insight into how HDAC4 exerts its neuroprotective effect and thus provide novel strategies to prevent neuronal loss in neurodegenerative conditions. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS058462-01A2
Application #
7524223
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Golanov, Eugene V
Project Start
2008-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
1
Fiscal Year
2008
Total Cost
$187,338
Indirect Cost
Name
University of Texas-Dallas
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800188161
City
Richardson
State
TX
Country
United States
Zip Code
75080
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