Characterization of the synthesis, metabolism, and release of novel endogenous catecholamines from human-derived cardiomyocytes, their effect on intracellular calcium levels, and identification of their receptors and transduction mechanisms.

• Grant number: 25/11569-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Gilberto de Nucci
• Grantee: Alex Henrique Miller
• Supervisor: Giuseppe Caliendo
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Università degli Studi di Napoli Frederico II (UNINA), Italy
• Associated to the scholarship: 24/08067-1 - Assessment of the stability of new endogenous catecholamines in biological liquids and identification of possible metabolites, BP.PD

Abstract

The recent discovery of endogenous dopamine analogues such as 6-nitrodopamine, 6-cyanodopamine, and 6-bromodopamine has opened a new frontier in understanding catecholamine signaling. Although their presence is established, a significant gap remains in elucidating their precise molecular targets and physiological roles, as well as their biosynthetic and metabolic pathways. Current research highlights their potent cardiovascular effects, with 6-nitrodopamine, for instance, showing significantly higher potency in elevating intracellular calcium in vascular smooth muscle cells compared to classical catecholamines. The primary objective of this project is to thoroughly characterize these novel derivatives by identifying their molecular targets and receptors specifically within human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. This highly relevant human-specific model is crucial for translational insights into their mechanisms and potential therapeutic implications. We'll achieve this through chemical pulldown assays coupled with advanced proteomics. Additionally, we'll map their biosynthetic and metabolic pathways via LC-MS/MS, and assess their functional impact on intracellular calcium and cAMP signaling. Ultimately, this integrated approach aims to advance our understanding beyond traditional catecholamine biology. (AU)