The long-term goal of this research is to elucidate the mechanisms of toxicant/hypoxia-induced cell injury and death. Our laboratory and others have shown that calpains, a family of Ca2 dependent proteases, play a critical role in toxicant/hypoxia-induced cell death. For example, a group of dissimilar calpain inhibitors prevented renal cell death produced by a diverse group of toxicants and promoted the return of respiration and active ion transport following hypoxia/reoxygenation. However, studies to date have not elucidated the mechanism of calpain activation under physiological or pathological conditions, nor have the critical intracellular targets of calpains during cell injury been identified. Previous reports indicate that the level of calpain phosphorylation may be an important determinant of activity. This proposal will test the central hypothesis that calpain dephosphorylation during hypoxic cell injury results in calpain-mediated mitochondrial dysfunction.
Specific Aim 1 will determine the level of calpain phosphorylation under control and hypoxia/reoxygenation conditions. In addition the activity of calpains with different levels of phosphorylation will be determined.
Specific Aim 2 will discover how calpains mediate mitochondrial dysfunction during hypoxia in situ and in isolated mitochondria, and identify the mitochondrial proteins targeted by calpains using proteomics/mass spectroscopy. Completion of these studies will increase our understanding of events that lead to hypoxic cell death, and aid in the development of therapeutic agents for the treatment of acute renal failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES011730-02
Application #
6626148
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Shreffler, Carol K
Project Start
2002-03-01
Project End
2003-07-18
Budget Start
2003-03-01
Budget End
2003-07-18
Support Year
2
Fiscal Year
2003
Total Cost
$16,618
Indirect Cost
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Arrington, David D; Van Vleet, Terry R; Schnellmann, Rick G (2006) Calpain 10: a mitochondrial calpain and its role in calcium-induced mitochondrial dysfunction. Am J Physiol Cell Physiol 291:C1159-71
Liu, Xiuli; Van Vleet, Terry; Schnellmann, Rick G (2004) The role of calpain in oncotic cell death. Annu Rev Pharmacol Toxicol 44:349-70