Programmed cell death and phospholipid asymmetry are two vitally important, distinct, and interconnected biological processes essential for normal cell functions and animal development. Defects in these two processes can cause various pathological conditions and human disease, including neurodegenerative disease, autoimmune disorders, and cancer. In this proposed work, we will carry out molecular genetic, reverse genetic, biochemical, cell biological, biophysical, and functional genomic analyses to decipher basic mechanisms that regulate apoptosis and phospholipid asymmetry during animal development. For the study of apoptosis, we hope to understand the regulatory mechanisms and signaling pathways that control the release of mitochondrial apoptogenic factors during apoptosis and identify new targets and downstream pathways of the cell death proteases that execute highly organized cell disassembly and rapid removal of the dying cells. For the study of phospholipid asymmetry, we plan to identify the molecular components and regulatory machineries that generate, maintain, and alter phospholipid asymmetry, focusing on understanding phosphatidylserine (PS) asymmetry. We will decipher the functions and roles of specific phospholipids to a cell and reveal the physiological and pathological consequences of altered phospholipid asymmetry to the cell and the animals. These studies should reveal novel mechanisms, pathways, and genes that control these two fundamental biological processes, and ultimately, provide new targets, ideas, and strategies to facilitate treatment of numerous human diseases caused by abnormalities in these two important processes.

Public Health Relevance

Apoptosis and lipid asymmetry in biological membranes are two vitally important, distinct, and interconnected biological processes essential for normal cell functions and organismal development. Defects in these two processes can cause various pathological conditions and human disease, including neurodegenerative disease, autoimmune disorders, and cancer. This proposal seeks to understand the mechanisms that regulate and execute these fundamental biological events and identify new genes and pathways important for these processes, leading to identification of new therapeutic targets or ideas to treat numerous human diseases caused by abnormalities in these two important processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118188-03
Application #
9491839
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Maas, Stefan
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
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
80303
Klöditz, Katharina; Chen, Yu-Zen; Xue, Ding et al. (2017) Programmed cell clearance: From nematodes to humans. Biochem Biophys Res Commun 482:491-497
Peng, Yu; Zhang, Man; Zheng, Lingjun et al. (2017) Cysteine protease cathepsin B mediates radiation-induced bystander effects. Nature 547:458-462
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
Rivera-Chávez, José; Raja, Huzefa A; Graf, Tyler N et al. (2017) Prealamethicin F50 and related peptaibols from Trichoderma arundinaceum: Validation of their authenticity via in situ chemical analysis. RSC Adv 7:45733-45751
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
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
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
Conradt, Barbara; Wu, Yi-Chun; Xue, Ding (2016) Programmed Cell Death During Caenorhabditis elegans Development. Genetics 203:1533-62
Wang, Yang; Zhang, Yi; Chen, Lianwan et al. (2016) Kinetics and specificity of paternal mitochondrial elimination in Caenorhabditis elegans. Nat Commun 7:12569
Zhou, Qinghua; Li, Haimin; Li, Hanzeng et al. (2016) Mitochondrial endonuclease G mediates breakdown of paternal mitochondria upon fertilization. Science 353:394-9