PRIN 2017 - PRIN20178YTNWC - Chiara Cencioni - The P2X7/NLRP3 Inflammasome Axis (DIT.AD010.045)

Thematic area

Engineering, ICT and technologies for energy and transportation

Project area

Structure responsible for the research project

Institute for system analysis and computer science "Antonio Ruberti" (IASI)

Project manager

CHIARA CENCIONI
Phone number: 0649937102
Email: chcencioni@gmail.com

Abstract

Low-grade chronic inflammation, triggered by hyperglycemia and expansion of visceral adipose tissue, is a hallmark of type 2 diabetes (T2D) and a major pathogenic factor of the disease and of its long-term
vascular complications. Inflammation is paralleled, caused, and amplified by a pathological accumulation of ATP in the extracellular compartment. Extracellular ATP, acting at P2 receptors (P2Rs), synergizes
with chemokines and adenosine (the main ATP degradation product) to drive inflammatory cell recruitment. Among P2R family members, the low affinity P2X7 receptor (P2X7R) subtype stands out for its
crucial role in inflammation.
While hyperglycemia is a well-known trigger for most of these responses, whether and to what extent the P2X7R is involved is unknown. Different small drug P2X7R antagonists are currently under phase I/II
clinical trials, and P2X7R-targeting antibodies and nanobodies have been developed and in vivo tested.
The main aim of this project is to define the role of extracellular ATP and the P2X7R/NLRP3 inflammasome axis in the pathogenesis of T2D and its microangiopathic and macroangiopathic complications.

Goals

The project will consist of in vitro and in vivo experiments aimed at investigating adipose tissue dysfunction, a major causative factor in T2D, and pathologic changes in selected T2D target tissues.
In detail, we will focus on the following in vitro studies:
1) effect of high glucose (HG) on P2X7R/NLRP3 epigenetic regulation and function in human and mouse adipocytes and monocytes/macrophages;
2) effect of P2X7R blockade or genetic deletion on HG-stimulated, microvesicule-mediated, release of inflammatory mediators from human and mouse adipocytes and monocytes/macrophages;
3) analysis of HG-induced mitochondrial dysfunction.
The in vivo phase will focus on the involvement of the P2X7R/NLRP3 inflammasome axis in the following changes associated to T2D:
(a) adipose tissue dysfunction;
(b) non-alcoholic fatty liver disease (NAFLD), a clinical condition that further impairs insulin resistance and glucose homeostasis;
(c) development and progression of renal and retinal injury;
(d) acceleration of atherosclerosis.
In conclusion, we propose to investigate the pathogenic role of the ATP/P2X7R/NLRP3 inflammasome system in T2D.

Start date of activity

29/08/2019

Keywords

inflammation, diabetes, P2X7

Last update: 20/04/2024