The Role of Mitochondrial VDACs in Apoptosis.

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DESCRIPTION (provided by applicant): Apoptosis is a form of directed cellular death that is essential for a variety of biological processes, including embryonic development, cancer surveillance, and host defense. Dysregulation of apoptosis occurs in many pathological states, including autoimmune disorders, malignancy, as well as acquired and heritable neurodegenerative disease. Two parallel pathways for apoptosis have been delineated; one mediated by cytochrome c release from the mitochondrial intermembrane space and a second pathway independent of cytochrome c release that activates caspase 8. The precise mechanism for cytochrome c release remains controversial, with evidence suggesting that the mitochondrial outer membrane channels, the voltage-dependent anion carriers (VDACs), are involved. In mammals there exist three VDAC isoforms. The Sponsor's laboratory has previously generated mouse cell lines deficient for each VDAC isoform. It is proposed to introduce mutant VDACs that are resistant to voltage-dependent closure into these cell lines and measure the kinetics and extent of apoptosis in these lines to define the precise role VDACs play in cytochrorne c mediated apoptosis.