The role of AGEs in activation of PRRs by gut microbiota from mice fed with a high-fat high-sucrose diet

• Grant number: 22/02829-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: December 01, 2022
• End date: November 30, 2023
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Silvana Auxiliadora Bordin da Silva
• Grantee: Caio Jordão Teixeira
• Supervisor: Andre Marette
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Université Laval, Canada
• Associated to the scholarship: 20/06397-3 - Study of cellular senescence in rodents subjected to Obesity, BP.PD

Abstract

The present proposal will be developed to expand the objectives of the original project that is being developed in Brazil (fellowship granted by FAPESP in Brazil - 2020/06397-3 - University of Sao Paulo), aiming to evaluate the role of advanced glycation end products (AGEs) in the cellular senescence of pancreatic beta cell of obese mice and mice with history of obesity. The aim is to take advantage of techniques based on Human Embryonic Kidney (HEK) 293 cells overexpressing different Pattern Recognition Receptors (PRRs) and in which the NF-kappaB responsive element is coupled to secreted Alkaline Phosphatase (SEAP). We will use these cells to assess the role of AGEs on TLR2, TLR4, NOD1 and NOD2 activation by gut microbiota from mice fed a high-fat high-sucrose (HFHS) diet. To achieve this goal, we will perform protocols in which mice will be fed a HFHS in combination with the inhibitor of AGEs synthesis (aminoguanidine). A protocol using the AGE precursor methylglyoxal will be also performed. The data on TLR2, TLR4, NOD1 and NOD2 activation by gut microbiota will be correlated with readouts for intestinal permeability (histological parameters of the intestinal epithelium, mucus content and ocludin1 expression). The present proposal will test the unprecedented notion that systemic factors resulting from chronic hyperglycemia might be able to shape gut microbiota to modulate of PRRs activity and intestinal permeability. (AU)