The basic mechanisms that underlie neurodegenerative diseases are unknown. Loss of function of specific regions of the brain is due to incapacitation of cells that constitute the specialized regions. Cells can simply stop functioning normally - neurons may cease to transmit signals - or they may die. There is now evidence that the pathology of several neurodegenerative diseases is due to inappropriate cell death, specifically, adventitious activation of apoptosis. This being the case, an understanding of the mediators of apoptosis, their identities and their role in orchestrating death, would be a vital step towards remedying the diseases. The apoptotic system is mediated by proteolytic enzymes that are responsible for conducting faithful execution of all responsive human cells. We propose to study neuronal apoptosis, and the proteolytic systems that contribute to it, in a simplified model that can be manipulated to answer basic issues of cell death pathways. The object of this proposal is to understand fundamental processes of cell death in cell culture models of human neurons and in primary rodent neurons. Specifically, we will focus on the pathways to apoptosis involving caspase family proteases in cell-free models of neuronal differentiation based on the neuronal-derived SHSY5Y cell line. We will use the knowledge gathered from these studies to examine apoptosis in rodent models of neuronal apoptosis, and specifically test the hypothesis that neuronal plasticity is in part due to activation of a localized apoptotic, protease-mediated program. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037878-08
Application #
7029737
Study Section
Special Emphasis Panel (ZRG1-SSS-P (01))
Program Officer
Sutherland, Margaret L
Project Start
1998-07-23
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
8
Fiscal Year
2006
Total Cost
$400,756
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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