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. Our research seeks a comprehensive understanding of molecular networks that support apoptotic cell death using the Drosophila model system. In the previous grant period we explored in vivo properties of the apoptosome, a pivotal molecular complex that lies at the heart of apoptotic pathways throughout the animal kingdom. Our analyses of apoptogenic mutants revealed conspicuous phenotypes and uncovered a form of collective cell death, where waves of apoptosis prompt the sudden elimination of epithelial tissue with features that resemble glandular involution and ischemic pathologies. We initiated a genetic dissection of this process and, in complementary efforts, we also completed a genome-wide screen for new apoptotic effectors. From these in vivo and ex vivo approaches, we captured novel gene sets that are obligate for cell death.
Our first aim leverages unique opportunities in this tractable model to investigate implicated factors and communal properties that govern collective apoptosis.
Aims 2 and 3 examine highly conserved genes not previously implicated in cell death.
Aim 2 starts with allelic mutations, arrested at an early step in collective apoptosis, and determines how the corresponding gene acts to control cell death.
Aim 3 starts with an effector required for caspase activation, advancing a comprehensive in vivo analysis of apoptotic functions specified by this gene product. These combined projects will advance general principles and novel determinants that regulate cell death in vivo. Because molecular pathways governing cell death are conserved, insights resulting from these efforts could illuminate new rationales for the treatment of neoplastic or degenerative pathologies, where misregulated apoptosis is a root cause.

Public Health Relevance

Apoptosis, a form of naturally occurring cell death, is firmly established in the cause and treatment of many human diseases including cancers and degenerative disorders. Our combined projects will advance general principles and identify genetic determinants that regulate cell death in vivo. Because molecular pathways governing apoptotic cell death are well conserved, insights resulting from our work may provide novel rationales for the treatment of diseases caused by the misregulation of apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM072124-16S1
Application #
8478399
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Maas, Stefan
Project Start
1995-05-15
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
16
Fiscal Year
2012
Total Cost
$5,716
Indirect Cost
$2,110
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
Wylie, Annika; Jones, Amanda E; Abrams, John M (2016) p53 in the game of transposons. Bioessays 38:1111-1116
D'Brot, A; Kurtz, P; Regan, E et al. (2016) A platform for interrogating cancer-associated p53 alleles. Oncogene :
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
Galluzzi, L; Bravo-San Pedro, J M; Vitale, I et al. (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 22:58-73
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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