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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 1 Study Section (DEV1)
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Maas, Stefan
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University of Texas Sw Medical Center Dallas
Anatomy/Cell Biology
Schools of Medicine
United States
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Vaisnav, Mahesh; Xing, Chao; Ku, Hung-Chih et al. (2014) Genome-wide association analysis of radiation resistance in Drosophila melanogaster. PLoS One 9:e104858
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
Link, Nichole; Kurtz, Paula; O'Neal, Melissa et al. (2013) A p53 enhancer region regulates target genes through chromatin conformations in cis and in trans. Genes Dev 27:2433-8
O'Neal, Melissa A; Posner, Bruce A; Coates, Craig J et al. (2013) A cell-based screening platform identifies novel mosquitocidal toxins. J Biomol Screen 18:688-94
D'Brot, Alejandro; Chen, Po; Vaishnav, Mahesh et al. (2013) Tango7 directs cellular remodeling by the Drosophila apoptosome. Genes Dev 27:1650-5
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Chen, P; Tu, X; Akdemir, F et al. (2012) Effectors of alcohol-induced cell killing in Drosophila. Cell Death Differ 19:1655-63
Lu, Wan-Jin; Chapo, Joseph; Roig, Ignasi et al. (2010) Meiotic recombination provokes functional activation of the p53 regulatory network. Science 328:1278-81
Chew, Su Kit; Chen, Po; Link, Nichole et al. (2009) Genome-wide silencing in Drosophila captures conserved apoptotic effectors. Nature 460:123-7
Joza, N; Galindo, K; Pospisilik, J A et al. (2008) The molecular archaeology of a mitochondrial death effector: AIF in Drosophila. Cell Death Differ 15:1009-18

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