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Screening and characterization of fluoroquinolone compounds and their influence on the biogenesis of miRNAs

Grant number: 16/24163-4
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2018
Effective date (End): February 28, 2021
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Marcelo Alves da Silva Mori
Grantee:Gerson Profeta de Souza
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):19/20554-7 - Investigation of mechanisms of miRNA biogenesis activation by the beta-adrenergic pathway, BE.EP.DR

Abstract

miRNAs are a class of small non-coding RNAs that act to regulate gene expression and are involved in diverse physiological and pathological processes. In adipose tissue, miRNAs appear to play a key role in metabolic homeostasis, as this tissue is an important source of circulating miRNAs and there is a decrease in the expression of these molecules and in components of their processing pathway, such as the type III endoribonuclease Dicer, in conditions of Obesity and aging. Several studies have attributed a fundamental role to Dicer in the development of metabolic diseases and longevity, since fat-specific Dicer knockout mice are more resistant to insulin and exhibit an increased risk of premature death. After Dietary Restriction (DR) it is possible to observe an increase of Dicer levels in adipose tissue of mice and in C. elegans nematodes. In the latter, Dicer overexpression in the intestine - an organ analogous to mammalian adipose tissue - protects worms against different types of stress and increases their lifespan. However, the use of restrictive diets in humans is difficult to apply chronically due to low compliance. In this sense, the search for pharmacologically active substances that are able to mimicking the effects of RD and act on the expression of proteins involved in miRNA processing becomes fundamental. Enoxacin, a fluoroquinolone compound with antibacterial action, is able to induce the production of miRNAs in eukaryotic cells by acting on the pre-miRNA processing step exerted by Dicer, and data from our laboratory indicate that this compound can prevent Obesity in mice and increase longevity in C. elegans if chronically administered. In this project, in partnership with the pharmaceutical company AstraZeneca, we aim to determine the potential of fluoroquinolones as Dicer agonists, in order to find safer and more effective pharmacological alternatives for in vivo RNAi pathway activation. (AU)