Molecular and Genetic Control of Programmed Cell Death

Ut Southwestern Medical Center, Dallas TX

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Abstract

Apoptosis is a universal feature of normal development and aging. This naturally occurring form of cell death is firmly established in the etiology, pathogenesis and treatment of many human diseases including cancers and degenerative disorders. Our research seeks a comprehensive understanding of molecular networks that support apoptotic cell death using the Drosophila model system. A central focus of our research examines in vivo properties of the apoptosome, a pivotal molecular complex that lies at the heart of apoptotic networks throughout the animal kingdom. Unexpected phenotypes seen in tissues mosaic for apoptogenic mutations revealed a conspicuous form of collective cell death, where waves of apoptosis coordinate sudden elimination of an entire epithelium with features that resemble glandular involution and ischemic pathologies. Our first aim leverages unique opportunities in this tractable model to investigate implicated factors and communal properties that govern collective apoptosis. We also initiated a genetic dissection of this process and, in complementary studies, we completed a genome-wide screen for new apoptotic effectors. From these in vivo and ex vivo approaches, we recovered novel gene sets encoding essential products that are obligate for apoptotic cell death. Projects in Aims 2 and 3 examine highly conserved members of these gene sets not previously implicated in cell death. Aim 2 starts with an allelic group, arrested at an early step in collective apoptosis, and determines how the corresponding gene acts to elicit cell death. Aim 3 starts with an effector required for caspase activation, advancing a comprehensive in vivo analysis of apoptotic functions engaged by this gene product. These combined projects will advance general principles and novel determinants that regulate cell death in vivo. Because molecular pathways governing apoptotic cell death are well conserved, insights resulting from these efforts may provide novel rationales for the treatment of diseases where misregulation of apoptosis is implicated.