Role of RAGE-NF-kB and RAGE-p38 MAPK axis on apoptosis and autophagy of immune and head and neck cancer cells

• Grant number: 11/06664-2
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2011 - October 31, 2013
• Field of knowledge: Health Sciences - Dentistry - Periodontology
• Principal Investigator: Carlos Rossa Junior
• Grantee: Carlos Rossa Junior
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

RAGE is a pattern-recognition receptor similar to Toll-like receptors (TLR) in their functions as activator of both innate and adaptive immunity. In contrast to TLRs, all known ligands of RAGE are of endogenous origin, release from cells under stress or in death processes, known as damage-associated molecular patterns (DAMPs). Since RAGE is sensible to cell death-derived ligands, signaling through RAGE plays a role in regulating processes related with cell survival: apoptosis and autophagy. However, the role of RAGE signaling in these processes varies in tumor and normal cells. Not much is known regarding the role of RAGE signaling on T lymphocytes, monocytes and in head and neck cancer cells. Our main hypothesis is that activation of RAGE has differential roles on the modulation of apoptosis and autophagy processes in immune and tumor cells. Our experimental strategy includes the determination of role RAGE-ligand interaction and the relative importance of p38 MAPK and NF-kB signaling (two major signaling pathways activated downstream of RAGE) on the survival of T lymphocytes, monocytes and head and neck cancer cells. We will use flow cytometry, biochemical assessment of mitochondrial function and immunofluorescence to characterize the apoptotic and autophagic processes on the different cell types. The relevance of this knowledge on RAGE role in cell survival is based on the possibility of using RAGE expression/signaling activity as a therapeutic target and/or prognosis indicator in conditions of infectious/inflammatory nature (e.g., periodontal diseases) and in head and neck cancer. Information generated by these studies can be used in future studies employing animal models of infectious, inflammatory diseases, diabetes and head and neck cancer. The specific aims proposed to test our main hypothesis are:1)To determine the role of RAGE activation on apoptosis of cells from innate and adaptive immunity and in head and neck cancer cells2)To assess the role of RAGE activation on autophagy in these same cell types (AU)