Dysregulation of apoptosis represents an underlying cause or contributor to many diseases. Activation of Caspase-family proteases is at the core of apoptotic cell death, representing a common point of intersection. A pathway for Caspase activation and apoptosis induction has been linked to stress in the Endoplasmic Reticulum (ER), though the mechanisms remain unclear. The ER serves a number of functions, including transport of glycoproteins destined for secretion and sequestration of intracellular Ca2+. ER-stress pathways linked to apoptosis may be important in ischemia-reperfusion injury, where Ca2+ escapes from the organelle during times of ATP deficiency, and in neurodegenerative diseases such as Alzheimer's and Parkinson's, where abnormalities in protein folding or secretion in the Golgi-ER compartment have been described. Our preliminary data suggested that an ER-associated, anti-apoptotic protein discovered by our laboratory, Baxinhibitor 1 (Bt-1), regulates apoptosis predominantly in the context of ER-stress situations. In this proposal, the role of Bl-1 in ER-stress will be extensively studied by addressing the following specific aims: (1) Dissect the point in apoptotic pathways where BI-1 blocks cell death induced by ER-stress. (2) Determine the effects of BI-1 on ER-dependent functions such as Ca2+ and protein sequestration. (3) Determine the role of BI-1 in regulating neuronal cell death during stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS047855-02
Application #
6886118
Study Section
Special Emphasis Panel (ZRG1-F03A (20))
Program Officer
Golanov, Eugene V
Project Start
2003-12-16
Project End
2006-12-15
Budget Start
2004-12-16
Budget End
2005-12-15
Support Year
2
Fiscal Year
2005
Total Cost
$49,928
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Xu, Chunyan; Xu, Wenjie; Palmer, Amy E et al. (2008) BI-1 regulates endoplasmic reticulum Ca2+ homeostasis downstream of Bcl-2 family proteins. J Biol Chem 283:11477-84
Xu, Chunyan; Bailly-Maitre, Beatrice; Reed, John C (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656-64
Chae, Han-Jung; Kim, Hyung-Ryong; Xu, Chunyan et al. (2004) BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol Cell 15:355-66