Chronic inflammation is a major cause of cancer, diabetes, and neurodegeneration. Inflammation is a complex topic, with both positive and negative effects on disease and therapy, and if we are to understand the pathological results and therapeutic benefits we need to better understand the mechanisms of where inflammation originates. The big picture in which this proposal is set is to understand the mechanisms of inflammation as they relate to regulated cell death. This application seeks to substantially advance current approaches, concepts, and technology to delve deeply into the inflammatory consequences of cell death and the connections between the cell death mechanisms. We combine biochemistry, cell biology, genome editing, non-animal models of inflammation, protein engineering, and chemical biology to explore linked pro- and anti- inflammatory cell death mechanisms. We propose that a robust and quantitative approach to defining inflammation is an important innovative quality of this proposal. The main goals of this proposal are to 1) compute the difference in inflammatory mediators released as a result of apoptosis, pyroptosis and necroptosis in macrophages, 2) define the mechanism of cytokine release from cells undergoing inflammatory cell death, and 3) understand the activation mechanisms of caspases in pyroptosis, and synthesize highly selective fluorescent probes to allow for direct visualization of specific caspase activation.

Public Health Relevance

Inflammation has both positive and negative functions in disease and disease therapy. This project seeks to explore fundamental links between regulated cell death mechanisms and the origins of inflammation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
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Sanford Burnham Prebys Medical Discovery Institute
La Jolla
United States
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Ramirez, Monica L Gonzalez; Poreba, Marcin; Snipas, Scott J et al. (2018) Extensive peptide and natural protein substrate screens reveal that mouse caspase-11 has much narrower substrate specificity than caspase-1. J Biol Chem 293:7058-7067
Kasperkiewicz, Paulina; Ko?t, Sonia; Janiszewski, Tomasz et al. (2018) Determination of extended substrate specificity of the MALT1 as a strategy for the design of potent substrates and activity-based probes. Sci Rep 8:15998
Ramirez, Monica L Gonzalez; Salvesen, Guy S (2018) A primer on caspase mechanisms. Semin Cell Dev Biol 82:79-85
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Kasperkiewicz, Paulina; Altman, Yoav; D'Angelo, Maximiliano et al. (2017) Toolbox of Fluorescent Probes for Parallel Imaging Reveals Uneven Location of Serine Proteases in Neutrophils. J Am Chem Soc 139:10115-10125
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Poreba, Marcin; Solberg, Rigmor; Rut, Wioletta et al. (2016) Counter Selection Substrate Library Strategy for Developing Specific Protease Substrates and Probes. Cell Chem Biol 23:1023-35
Brumatti, Gabriela; Ma, Chunyan; Lalaoui, Najoua et al. (2016) The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci Transl Med 8:339ra69
Salvesen, Guy S; Hempel, Anne; Coll, Nuria S (2016) Protease signaling in animal and plant-regulated cell death. FEBS J 283:2577-98

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