Artificial Intelligence in the Identification of Cardiovascular Molecular Targets in Gender-Affirming Hormone Therapy with Testosterone

• Grant number: 24/18205-2
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2025
• End date: March 31, 2028
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: Rita de Cassia Aleixo Tostes Passaglia
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Ana Claudia de Souza ; Andre de Souza Mecawi ; Fernando Silva Carneiro ; Jeimison Duarte Santos ; Marcio Dorn ; Maria Cátira Bortolini ; Pedro Vargas Pinilla

Abstract

Transgender individuals - who have a gender identity different from the one assigned to them at birth - seek medical assistance to undergo gender transition, a multidisciplinary process that encompasses physical, biological and social changes. Hormone therapy is a primary strategy for obtaining secondary sexual characteristics aligned with an individual's gender identity. Testosterone, used in gender-affirming hormone therapy (THAG-T), promotes the development of male secondary sexual characteristics, but also affects the cardiovascular system, increasing blood pressure, causing dyslipidemia and endothelial dysfunction. The scarcity of robust clinical and preclinical studies is one of the main limiting factors for elucidating the mechanisms underlying the cardiovascular effects of THAG-T. Our proposal, by integrating bioinformatic analysis of data from transgender men and advanced artificial intelligence (AI) algorithms with RNA-seq single nuclei analysis in an experimental model of THAG-T (female mice treated with testosterone), will allow us to: i) Determine the changes induced by testosterone in the cardiovascular system of individuals undergoing THAG-T by analyzing available databases, ii) Identify changes induced by testosterone in cells of the cardiovascular system of the THAG-T experimental model iii) Characterize the set of changes in humans that overlap with the changes observed in the experimental model, iv) Validate potential molecular targets identified in bioinformatics analyses, carrying out in vitro and in vivo functional studies. Our hypothesis is that testosterone will modify the expression of genes with an important role in controlling the cardiovascular system both in humans and in the experimental model of THAG-T with a high degree of homology. The bioinformatics analysis will reveal potential targets and direct the investigation of the mechanisms by which testosterone impacts the cardiovascular system. The multidisciplinary and translational approach will allow us to deepen our knowledge on the effects of testosterone in the cardiovascular system, both in humans and in the experimental model. It will provide valuable information for understanding the molecular mechanisms involved in the actions of testosterone, and may reveal markers of cardiovascular risk with potential to increase the safety and effectiveness of hormonal therapies for transgender men. (AU)