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Modulation of the necroptotic pathway and its pathophysiological relevance


Recently, a novel cell death pathway was identified and named necroptosis. This cell death type resembles the accidental necrosis regarding its morphology and the release of the cytoplasmic contents following the plasma membrane rupture. On the other hand, its induction and execution are biochemically controlled, and it involves the activation of the RIPK3 kinase which, in turn, activates MLKL, the effector molecule of this cell death type. The sensitivity to necroptosis of a given tissue or cell type is correlated to the expression levels of these molecules as well as their inhibitors, such as caspase-8, FADD and c-FLIP. To date, little is known about the mechanisms that modulate the expression of RIPK3 and MLKL despite the evidence that their levels vary upon different pathophysiological settings, like ischemia-reperfusion, viral infection and cancer. The major goal of this project is to investigate the mechanisms involved in the expression and activation of RIPK3 and MLKL and their relevance to the pathophysiological processes, especially cancer. This study will be divided in two major axes. The first axis will focus on the RIPK3 and MLKL transcriptional regulation through promoter activity studies and the investigation of the transcription factors and biochemical pathways involved in this process. These findings will be used to understand the distinct expression levels of RIPK3 and MLKL in different cancer types as well as to the sensitization of these cells to necroptosis induction via exogenous intervention. The second axis will be focused in the discovery and characterization of alternative pathways of MLKL activation that do not require RIPK3. Our preliminary results have identified compounds that are able to induce this alternative pathway; their therapeutic potential will be examined in conditions wherein RIPK3 expression is absent, such as breast cancer and melanoma. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
VERGARA, GUILHERME AFONSO; EUGENIO, GISELE CRISTINE; FLEURY MALHEIROS, SUZANA MARIA; VICTOR, ELIVANE DA SILVA; WEINLICH, RICARDO. RIPK3 is a novel prognostic marker for lower grade glioma and further enriches IDH mutational status subgrouping. JOURNAL OF NEURO-ONCOLOGY, v. 147, n. 3 MAR 2020. Web of Science Citations: 0.

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