Molecular and Genetic Control of Programmed Cell Death

Ut Southwestern Medical Center, Dallas TX

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Abstract

DESCRIPTION (provided by applicant): Apoptosis is a universal feature of normal development and aging. This form of cell death is firmly established in the pathogenesis and treatment of many human diseases, including cancer, AIDS, neurodegenerative disorders, auto-immunities and cardiovascular disease. In many ways, and despite extensive research, our knowledge of apoptotic cell death in biological systems and in the clinic is incomplete. Our research seeks a comprehensive understanding of molecular networks that support cell death in vivo using sophisticated experimental tools and unique opportunities available in the Drosophila system. Throughout the animal kingdom, a universally conserved molecular machine referred to as the apoptosome lies at the heart of apoptotic networks. In canonical models, this complex functions as a platform to launch a cascade of proteases known as caspases that, in turn, promote self-destruction. However, it is also now widely appreciated that the apoptosome does not inevitably provoke cell suicide but can, instead, also act to remodel cells, supporting a wide range of adaptive physiological functions such as hematopoiesis and synaptic plasticity. Determinants that specify whether the apoptosome acts to kill or remodel have not been identified and prevailing models do not explain how the apoptosome functions without provoking cell death. We confront these and related questions by capitalizing on Tango7, a new regulator of apoptosome-dependent cell death that we discovered in the current grant period. Tango7 is highly conserved and is one of just a few proteins that promotes apoptosome activity in vitro and is also required for caspase activity, cell death and remodeling in vivo. By leveraging this unique entry point, we integrate genetic and biochemical approaches to examine apoptosome function as it collaborates with Tango7 to support cell killing and promote cell remodeling. Our aims will advance novel determinants and general principles that control cell death and other caspase- dependent functions in vivo. Because molecular pathways governing these processes are well conserved, insights resulting from this initiative could facilitate novel rationales for the treatmnt of diseases where aberrant caspase activity and cell death are implicated.