Role of RAGE-NFkB and RAGE-p38 MAPK axis on apoptosis of innate and apative immune cells

• Grant number: 11/07261-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2011
• End date: March 31, 2013
• Field of knowledge: Health Sciences - Dentistry - Periodontology
• Principal Investigator: Carlos Rossa Junior
• Grantee: Maíra Nathalia Lache
• 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 apoptotic processes. However, there is paucity of information regarding the role of RAGE signaling on apoptosis of T lymphocytes and monocytes. Our main hypothesis is that activation of RAGE has a relevante role on the modulation of apoptosis in innate and adaptive immune 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 and monocytes. We will use flow cytometry and biochemical assessment of mitochondrial function to characterize the intrinsic and extrinsic apoptotic pathways in these cell types. The relevance of this knowledge on the role of RAGE in the apoptosis of immune cells is related with 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), particularly associated with conditions with increased accumulation of DAMPs (e.g., ageing and diabetes). Information generated by these studies can be used in future studies employing animal models of infectious/ inflammatory diseases. This proposal is part of a larger study aiming to determine and further characterize the role of RAGE signaling on apoptosis and autophagy in immune and head and neck cancer cells. The specific aim proposed to test our main hypothesis is:- To determine the role of RAGE activation on apoptosis of cells from innate and adaptive immunity