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Role of extracellular vesicles produced during exercise in the prevention of NASH and HCC

Grant number: 19/18223-2
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): February 03, 2020
Effective date (End): February 02, 2021
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Alice Cristina Rodrigues
Grantee:Mariana de Mendonça
Supervisor abroad: Mark Febbraio
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : Monash University, Australia  
Associated to the scholarship:17/19513-9 - Role of microRNAs in the regulation of adipokines and myocynes: understanding molecular mechanisms involved in the interaction between adipose tissue and skeletal muscle, BP.DD

Abstract

Non-alcoholic steatohepatitis (NASH) represents an aggressive form within the spectrum of non-alcoholic fatty liver disease (NAFLD) that could further progress to hepatic fibrosis, cirrhosis and even the development of hepatocellular carcinoma (HCC). However, no drugs have been approved specifically for the prevention or treatment of NASH, mainly because it is difficult to decipher the molecular mechanisms underlying the pathogenesis of NASH and understand how it progresses to HCC by studying humans. Consequently, progress in this field depends on the availability of reliable preclinical models that are amenable to genetic and functional analyses and exhibit robust NASH to HCC progression. It is already been demonstrated that MUP-uPA mouse is a model of NASH driven HCC that mimics human disease, also preliminary results from Professor Febbraio's group demonstrated that exercise ameliorate NASH development and progression in MUP-uPA mice fed a high-fat diet. Recently, Professor Febbraio's group demonstrated that extracellular vesicles (EVs) are released into the circulation with exercise, and pulse-chase and intravital imaging experiments suggested EVs liberated by exercise have a propensity to localize in the liver and can transfer their protein cargo. This raised the possibility that EV transfer may be one potential therapeutic strategy for treating NASH. So the objective of this study is to test the hypothesis that exosomal transfer from exercised donor mice will prevent the progression of NASH in the MUP-uPA mouse model.