Contribution of the Timd4 gene in heart rate regulation in mice

• Grant number: 24/16421-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2024
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Genetics - Animal Genetics
• Principal Investigator: Samantha Kuwada Teixeira
• Grantee: Barbara Sganga
• 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

Cardiovascular diseases (CVD) are considered the leading cause of death in the world. Currently, heart rate (HR) is considered a truly modifiable risk factor for CVD. Heart rate is a complex phenotype, therefore it is determined by multiple environmental, genetic and endogenous factors. It is estimated that the genetic contribution in this phenotype corresponds to 26-32% of the interindividual variation. Recently, our group used N-ethyl-N-nitrosurea-induced germline mutagenesis combined with automatic meiotic mapping to identify new genes involved in HR regulation. We analyzed over 43,000 third-generation animals from more than 800 families to evaluate more than 45,000 genetic variants in 15,000 genes and identified 144 candidate genes that affect the HR phenotype, of which only 26 were already known. Among the 118 new candidate genes, we identified the Timd4 gene, whose mutation associated with phenotype alteration occurs in the protein domain, affecting its conformation and function according to computational analyses. The present project aims to evaluate whether the absence of the Timd4 gene in genetically modified mice results in the alteration of the cardiac phenotype, promoting a decrease in heart rate accompanied by arrhythmia. To this end, knockout animals for the gene will be acquired from a specialized company and a colony of this strain will be developed in our laboratory. The genetically modified animals will have their cardiac function evaluated under baseline conditions and under stress by plethysmography and electrocardiogram (ECG). The results of this project will allow a profound study of the contribution of this gene in the regulation of heart rhythm in mice.