Gene modulation of RIPK3 and MLKL and its impact in the sensitivity to death by necroptosis

• Grant number: 16/06757-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2016
• End date: February 28, 2018
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Ricardo Weinlich
• Grantee: Larissa Cardoso Zanetti
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Necroptosis is a recently discovered, biochemically-controlled, cell death pathway that is independent of caspases and present morphological hallmarks similar to those of accidental necrosis. It can be activated by different stimuli, including death receptors and TRIF-mediated signals, and involves sequential phosphorylation of RIPK1 and RIPK3 kinases as well the MLKL pseudokinase. The role of necroptosis was already demonstrated in many pathophysiological conditions, including bacterial and viral infections, cancer, ischemic insults and autoimmune disease. In many of these settings, the levels of RIPK3 and MLKL expression was shown to vary significantly, either positively or negatively. Also, these levels correlated to the sensitivity towards necroptotic stimuli. Surprisingly, however, there is no report so far concerning the signaling pathways and transcription factors involved in this regulation nor the characterization of RIPK3 and MLKL promoter regions. Therefore, this project has the objective of shedding light on the mechanisms of RIPK3 and MLKL transcriptional modulation through promoter region studies as well the characterization of the transcription factors involved in their regulation.