Mitochondria play important roles in apoptosis and other forms of cell death. These energy producing organelles appear to be the major target of regulation by Bc1-2 family proteins, a group pro-apoptotic and anti-apoptotic proteins which integrate into mitochondrial membranes. Though much information has been gained in recent years about the molecular mechanisms by which mitochondria participate in apoptotic cell death, several questions remain unanswered. The goal of this proposal is to provide a better understanding of the fundamental mechanisms used by Bc1-2 (anti-apoptotic), Bax (pro-apoptotic), and selected additional members of the Bc1-2 family in the control of mitochondrial functions relevant to cell life and death. Among the questions that will be addressed are: (1) What are the mechanisms responsible for release into the cytosol of apoptogenic proteins stored within mitochondria during apoptosis?; (2) How is the pore-forming activity of Bc1-2 and Bax related to their ability to induce or suppress release of apoptogenic proteins from mitochondria?; (3) Do interactions of Bc1-2 and Bax with components of the mitochondrial permeability transition pore play a critical role in their mechanisms of action?; (4 What controls the transition of Bax from latent to active protein? Because dysregulation of mitochondria-dependent cell death pathways makes major contributions to illnesses characterized by either insufficient cell eradication (e.g. cancer, autoimmunity) or excessive cell destruction (e.g. myocardial infarction, stroke; AIDS; neurodegeneration), the insights gains from these investigations could find broad applicability to the improved treatment of several human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM060554-01
Application #
6038288
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
2000-02-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$415,062
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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