As a normal aspect of animal development and homeostasis, programmed cell death (apoptosis) plays an essential role in maintaining the physiological balance of appropriate cell numbers by opposing uncontrolled cell proliferation. Abnormal inactivation or activation of apoptosis can lead to uncontrolled cell growth or uncontrolled cell death and may result in human diseases such as cancer, neurodegenerative diseases, and autoimmune disorders. The broad, long-term objective of this application is to understand the molecular mechanisms underlying the control and the execution of apoptosis and to use the knowledge from the study of apoptosis to facilitate development of new methods in treatment and prevention of human diseases caused by inappropriate cell death. Apoptosis is controlled and executed by an evolutionarily conserved cell death pathway. At the heart of this pathway is a family of highly specific """"""""cell death"""""""" proteases, the caspases, which are first synthesized as inactive protease precursors and later activated through proteolysis during apoptosis. The activation of cell death proteases triggers systematic and orderly cell-disassembly of apoptotic cells and their removal by phagocytes. Several sensitized genetic screens, candidate-based reverse genetic screens, and biochemical screens have been carried out to identify CED-3 protease substrates and downstream components and pathways that trigger and coordinate the cell-disassembly and removal events. These studies have led to the identification of 20 new cell death genes and several candidate CED-3 substrates that act downstream of, or in parallel to, CED-3 to mediate various cell death execution processes, including chromosome fragmentation, mitochondria elimination, cell corpse recognition/engulfment, and other yet to be identified cell death signaling and execution events.
The specific aims of this application are to: (1) characterize the functions of candidate CED-3 substrates in cell death execution;(2) identify and characterize additional genes involved in phosphatidylserine externalization, an """"""""eat-me"""""""" signal, during apoptosis;(3) characterize genes involved in cell corpse recognition/engulfment and their acting mechanisms;and (4) characterize genes that affect other cell death execution processes. These studies should allow us to systematically identify molecular components and pathways involved in cell death execution and their functioning mechanisms. Some of the molecules identified in these studies may turn out to be potential targets for therapeutic drug designs in curing cancers or other human diseases caused by inappropriate apoptosis.

Public Health Relevance

Programmed cell death (apoptosis) plays an essential role in animal development and tissue homeostasis by maintaining appropriate cell numbers. Abnormal inactivation or activation of apoptosis can lead to uncontrolled cell growth or uncontrolled cell death and may result in human diseases such as cancer, neurodegenerative diseases, and autoimmune disorders. The broad, long-term objective of this application is to understand the molecular mechanisms controlling the activation and execution of apoptosis and to use the knowledge from these studies to facilitate development of new methods in treatment and prevention of human diseases caused by inappropriate cell death. Apoptosis is controlled and executed by an evolutionarily conserved family of highly specific cell death proteases, the caspases. The activation of cell death caspases triggers systematic and orderly cell- disassembly of apoptotic cells and their removal by phagocytes. We have used both genetic and biochemical methods to identify proteins that are cleaved by the CED-3 cell death protease to trigger and coordinate various cell-killing events. Some of the molecules identified in these studies may turn out to be potential targets for therapeutic drug designs in curing cancers or other human diseases caused by inappropriate apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059083-11
Application #
7778234
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Zatz, Marion M
Project Start
1999-07-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
11
Fiscal Year
2010
Total Cost
$356,050
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Smith, Christina E; Soti, Subada; Jones, Torey A et al. (2017) Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors. Cell Chem Biol 24:281-292
Zhao, Pei; Zhang, Zhe; Lv, Xiaoying et al. (2016) One-step homozygosity in precise gene editing by an improved CRISPR/Cas9 system. Cell Res 26:633-6
Lin, Jason L J; Nakagawa, Akihisa; Skeen-Gaar, Riley et al. (2016) Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G. Cell Rep 16:279-287
Chen, Xudong; Wang, Yue; Chen, Yu-Zen et al. (2016) Regulation of CED-3 caspase localization and activation by C. elegans nuclear-membrane protein NPP-14. Nat Struct Mol Biol 23:958-964
Wang, Yang; Zhang, Yi; Chen, Lianwan et al. (2016) Kinetics and specificity of paternal mitochondrial elimination in Caenorhabditis elegans. Nat Commun 7:12569
Conradt, Barbara; Wu, Yi-Chun; Xue, Ding (2016) Programmed Cell Death During Caenorhabditis elegans Development. Genetics 203:1533-62
Zhou, Qinghua; Li, Haimin; Li, Hanzeng et al. (2016) Mitochondrial endonuclease G mediates breakdown of paternal mitochondria upon fertilization. Science 353:394-9
Sullivan, Kelly D; Nakagawa, Akihisa; Xue, Ding et al. (2015) Human ACAP2 is a homolog of C. elegans CNT-1 that promotes apoptosis in cancer cells. Cell Cycle 14:1771-8
Neumann, Brent; Coakley, Sean; Giordano-Santini, Rosina et al. (2015) EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature 517:219-22
Yang, Hengwen; Chen, Yu-Zen; Zhang, Yi et al. (2015) A lysine-rich motif in the phosphatidylserine receptor PSR-1 mediates recognition and removal of apoptotic cells. Nat Commun 6:5717

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