MiRNA expression profile of Pkd1 haploinsufficient animal model

• Grant number: 19/04672-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2019
• End date: November 30, 2019
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Frederico Moraes Ferreira
• Grantee: Larissa Paraiso da Silva
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

The purpose of the current project is to perform the analysis of the renal miRNA expression profile of Pkd1 (the mutated gene in the Autosomal Dominant Polycystic Kidney Disease - ADPKD) haploinsufficient animal model. ADPKD is the most common renal monogenic disorder with population prevalence from 1:400 to 1:1000. It is characterized by progressive, bilateral renal cystic expansion followed by gradual loss of renal function, while its systemic nature is reflected by extra-renal manifestations typically involving liver and the cardiovascular system. It is a very severe and debilitating infirmity which patients evolve to the end stage renal disease at 54 years old and begin hemodialic therapy or transplantation. It is, therefore, a highly relevant medical, social and economic disorder for the country and of extreme interest for the scientific community. Cyst formation is triggered by mutations in the PKD1 or PKD2 genes, which encode, respectively, to polycystin-1 (PC1) and polycystin-2 (PC2). The first likely works as transmembrane mechanic-sensor receptor. PC2, in turn, is a non-selective cationic channel permeable to calcium. These two proteins interact to each other and with other binding proteins to perform activation/inactivation events of molecular pathways of calcium regulation, apoptosis and cell proliferation. Indeed, disruption of polycystins interactions with components of Wnt, mTOR, STAT3 and JAK2/STAT1 pathways is translated into a number of intracellular pathway abnormalities. Defects in the mentioned pathways can also impact oriented cell division, contributing to cyst growth. The goal of the present study is to determine the differentially expressed miRNAs, genes and molecular pathways associated to the ADPKD animal model. This kind of study has been employed to discovery of potential diagnostic, progression and prognostic markers of several diseases, as well as for identification of new therapeutic targets. In the present context, it is hope to contribute for the comprehension of the molecular mechanisms of the ADPKD, particularly, in scenarios which there is loss of function of one of the allelic genes related the disease. For that, the miRNAs differential expression analysis will be done in the Pkd1+/- haploinsufficient model. The expected results include the identification of differentially expressed miRNAs responsible for the fundamental characteristics represented in the animal model; and possibly the identification of genes and molecular pathways associated to progression, prognostic and potential therapeutic targets for the ADPKD.