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.

Public Health Relevance

Apoptosis, a form of naturally occurring cell death, is firmly established in the cause and treatment of many human diseases including degenerative disorders and cancers. Our research advances general principles and identifies molecular determinants that control cell death in normal and pathologic settings. Because mechanisms that regulate this form of cell suicide are well conserved, insights resulting from our work may lead to novel rationales for the diagnosis and treatment of various diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072124-19
Application #
8725677
Study Section
Special Emphasis Panel (ZRG1-CB-W (02))
Program Officer
Maas, Stefan
Project Start
1995-05-15
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
19
Fiscal Year
2014
Total Cost
$397,500
Indirect Cost
$147,500
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Wylie, Annika; Jones, Amanda E; D'Brot, Alejandro et al. (2016) p53 genes function to restrain mobile elements. Genes Dev 30:64-77
Jiang, Dadi; LaGory, Edward L; Kenzelmann Brož, Daniela et al. (2015) Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function. Cell Rep 10:1096-109
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Ziraldo, Riccardo; Link, Nichole; Abrams, John et al. (2015) Towards automatic image analysis and assessment of the multicellular apoptosis process. IET Image Process 9:424-433
Garcia-Hughes, Gianella; Link, Nichole; Ghosh, Anwesha B et al. (2015) Hid arbitrates collective cell death in the Drosophila wing. Mech Dev 138 Pt 3:349-55
Link, Nichole; Abrams, John M (2014) DNA loops specify p53 network responses. Cell Cycle 13:1659
Wylie, Annika; Lu, Wan-Jin; D'Brot, Alejandro et al. (2014) p53 activity is selectively licensed in the Drosophila stem cell compartment. Elife 3:e01530
Vaisnav, Mahesh; Xing, Chao; Ku, Hung-Chih et al. (2014) Genome-wide association analysis of radiation resistance in Drosophila melanogaster. PLoS One 9:e104858

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