Characterization of a new candidate gene involved in the heart rate control and development of cardiovascular risk: KAPTIN (Kptn)

• Grant number: 19/11502-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2019
• End date: July 31, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: José Eduardo Krieger
• Grantee: Anna Laura Viacava Américo
• 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: 14/50889-7 - National Institute of Science and Technology Medicine Assisted by Scientific Computing (INCT-MACC), AP.TEM

Abstract

Cardiovascular Diseases (CVD) are considered the leading cause of death in the world. Heart Rate (HR) is a modifiable risk factor for CVD. Using "forward genetic screen" we selected Kptn gene among 94 candidate genes that influence HR. Preliminary results suggest that the gene is necessary for maintenance of intrinsic HR only in females. Thus, we will test the hypothesis that the Kptn gene influences the cardiovascular risk in female through its influence on the control of the intrinsic HR and the association of potential biochemical pathways. We will develop and characterize Knockout (KO) mice for the Kptn gene to validate the contribution of the gene to HR. The influence of sex on the phenotype will be investigated in animals through ovariectomy and therapies that affect sex hormones. We will investigate, through gene expression analysis, candidate cardiac pathways influenced by the presence and absence of Kptn. These studies will be complemented by analyzing the phenotype in adult embryonic development using reverse genetic screening in Zebrafish. Finally, we will investigate whether individuals with extreme phenotypes (arrhythmias) have enrichment of rare pathogenic mutations in the Kptn gene compared to the general population. If initial results are confirmed, we will test the hypothesis that decreased expression of this gene confers cardiovascular susceptibility in females by increasing experimental post-infarction mortality in mice. Thus, we believe that the present project uses integrated approaches to characterization of a candidate gene that can have great impact as a factor of susceptibility to cardiovascular diseases, especially in female subjects. (AU)