Abstract

This is a proposal to investigate the biochemical mechanisms of cell necrosis. The mitochondrial permeability transition (MPT) has been established as a key event in hepatocyte cell death caused by agents that inhibit mitochondrial electron transport and in cell death in L929 fibroblasts caused by tumor necrosis factor (TNF). The objectives of the proposal are to identify events leading to the MPT and to determine how induction of the MPT ultimately causes changes in the cytoskeleton and the plasma membrane that result in necrosis. The first specific aim is to establish the mechanism of induction of the MPT. The role of long-chain fatty acyl CoA in de-energizing mitochondria will be investigated in hepatocytes, whereas the roles of mitogen activated protein kinases (MAPKs) will be investigated in the L929 cells.
Specific aim 2 will investigate the hypothesized coupling of the MPT to changes in cytoskeletal proteins. Both biochemical and morphologic studies are proposed.
In Specific aim 3, the role of phospholipase activation in causing plasma membrane alterations will be investigated. These studies will employ phospholipase A2 inhibitors and analyses of phospholipase activities in plasma membrane fractions.
In Specific aim 4, changes in the molecular order of plasma membranes will be investigated with spin labeling methods and changes in ion permeability will be examined.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038305-13
Application #
2734057
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1986-07-01
Project End
2001-06-30
Budget Start
1998-07-15
Budget End
1999-06-30
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

Dosch, Natalie C; Guslits, Elyssa F; Weber, Morgan B et al. (2016) Maternal Obesity Affects Inflammatory and Iron Indices in Umbilical Cord Blood. J Pediatr 172:20-8
Tafani, Marco; Karpinich, Natalie O; Serroni, Ada et al. (2006) Re-evaluation of the distinction between type I and type II cells: the necessary role of the mitochondria in both the extrinsic and intrinsic signaling pathways upon Fas receptor activation. J Cell Physiol 208:556-65
Karpinich, Natalie O; Tafani, Marco; Schneider, Timothy et al. (2006) The course of etoposide-induced apoptosis in Jurkat cells lacking p53 and Bax. J Cell Physiol 208:55-63
Tafani, Marco; Karpinich, Natalie O; Hurster, Kathryn A et al. (2002) Cytochrome c release upon Fas receptor activation depends on translocation of full-length bid and the induction of the mitochondrial permeability transition. J Biol Chem 277:10073-82
Karpinich, Natalie O; Tafani, Marco; Rothman, Ronald J et al. (2002) The course of etoposide-induced apoptosis from damage to DNA and p53 activation to mitochondrial release of cytochrome c. J Biol Chem 277:16547-52
Tafani, Marco; Cohn, Joshua A; Karpinich, Natalie O et al. (2002) Regulation of intracellular pH mediates Bax activation in HeLa cells treated with staurosporine or tumor necrosis factor-alpha. J Biol Chem 277:49569-76
Tafani, M; Minchenko, D A; Serroni, A et al. (2001) Induction of the mitochondrial permeability transition mediates the killing of HeLa cells by staurosporine. Cancer Res 61:2459-66
Pastorino, J G; Tafani, M; Farber, J L (1999) Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinase-dependent pathway. J Biol Chem 274:19411-6
Pastorino, J G; Tafani, M; Rothman, R J et al. (1999) Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem 274:31734-9
Pastorino, J G; Chen, S T; Tafani, M et al. (1998) The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 273:7770-5

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