Designing a new therapeutic approach using exosomal miRNAs to target metabolic disease: ApoB and PCSK9 inhibition effects in reducing atherosclerosis risk as a model system

• Grant number: 20/12766-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): August 15, 2021
• Effective date (End): February 14, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Mario Jose Abdalla Saad
• Grantee: Tamires Marques Zanotto
• Supervisor: Carl Ronald Kahn
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Research place: Harvard University, Boston, United States
• Associated to the scholarship: 19/16858-0 - Designing a new therapeutic approach using exosomal miRNAs to target metabolic disease: APOB and PCSK9 inhibition effects in reducing atherosclerosis risk as a model system, BP.PD

Abstract

MicroRNAs are small non-coding RNAs that can regulate gene expression being released into the circulation where they are carried by ribonucleoproteins, lipoproteins, extracellular vesicles or exosomes. Studies have shown an advantage of exosomes over artificial liposomes for RNA transport due to their higher capacity of endocytosis and protection against phagocytosis. In addition, although there is a basal release of miRNAs, several publications have shown that exosome trafficking and release of the cargo can increase with certain stimuli, including by inflammatory states. Recent work from the hosting lab has provided important evidence about the existence of an adipose tissue-liver communication axis based on circulating exosome-contained miRNAs. The aim of this study is to further explore this communication axis, including the miRNA loading mechanism in exosomes, and investigate whether exosomal miRNAs could be used to treat metabolic diseases originated in the liver. As a model case, we have selected hypercholesterolemia and atherosclerosis, that originates from cholesterol deposition and plaque accumulation in the arteries. Cholesterol is mostly transported by LDL lipoproteins, whose main protein component is apolipoprotein B-100. Several studies have already shown the important role of ApoB-100 inhibition as a target for dyslipidemia and cardiovascular risk therapy. In addition, we also aim to target the proprotein convertase subtilisin/kexine type 9 (PCSK9), which is an enzyme that degrades LDL-receptor in hepatocytes. It´s inhibition leads to increased LDL receptor levels, lowering LDL-cholesterol in the circulation. We propose the development of an innovative therapeutic design by making use of the high efficiency of miRNAs in inhibiting specific targets and the novel adipose tissue-liver communication axis via circulating exosomes. (AU)