Blood pressure control genes characterization and localization through the ENU methodology

• Grant number: 17/05352-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2017
• End date: January 31, 2020
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: José Eduardo Krieger
• Grantee: Roberto Braz Pontes Junior
• 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
• Associated research grant: 13/17368-0 - Cardiovascular genomics: mechanisms & novel therapeutics - CVGen mech2ther, AP.TEM
• Associated scholarship(s): 17/14448-4 - Identification and characterization of genes controlling blood pressure by the ENU methodology, BE.EP.PD

Abstract

Hypertension affects one billion people worldwide, being the biggest risk factor for cardiovascular disease. Among hypertensive patients, about 95% are characterized by primary or essential hypertension, which causes remain unknown. The genetic factor is very important in this type of hypertension, considering that the heritability of the systolic and diastolic blood pressure varies from 25 to 68%, according to the population. Genomic strategies in humans have revealed more than 100 genetic variants associated with blood pressure control and hypertension. However, these variants individually or collectively account for only 1-2% of the variation in blood pressure in humans. Contributing to the difficulty of identifying the cause of essential hypertension, studies of mapping and refinement of quantitative traits in rats have shown limited results despite the great time and resources expended. Wang and co-workers recently described a methodology using the targeted phenotype approach providing a bioinformatics tool capable of rapidly analyzing genotypic and phenotypic results in order to provide a robust association between the results. Thus, the aim of this work is to characterize blood pressure regulating genes by the directed phenotype approach and ENU. To that end, all mutations caused by the ENU will be identified by sequencing the exon of the G1 progenitor and its zygosity will be established in the G2/G3 mice before the phenotypic evaluation. G3 animals will be submitted to blood pressure assessment by caudal plethysmography, between 10-14 weeks of life. Quantitative blood pressure traits will then be analyzed with Linkage Analyzer software in single pedigrees or by considering multiple pedigrees, detecting the significant link between individual mutations and aberrant scores on the phenotype. Once the relationship is established, confirmation will be provided by the development and study of knockout animals. Considering this previously established procedure to generate and phenotype mutant animals, in addition to the fact that positional cloning will be finished when the phenotyping of the animals is completed, we believe that this strategy will uniquely allow the systematic characterization of blood pressure regulating genes in mice. (AU)