Immunological Dysfunction Biological and Clinical Implications in Telomere Biology Disorders

• Grant number: 24/17942-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Aruna Barade
• Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Ribeirão Preto , SP, Brazil

Abstract

Telomeres, essential structures at chromosome ends, comprise repetitive non-coding DNA sequences that protect genome stability. Each DNA replication cycle shortens telomeres, leading to cellular aging and dysfunction. Telomerase, an enzyme crucial for telomere maintenance, comprises TERT and TERC components and associated proteins that together elongate telomeric DNA. Dysfunction in telomere maintenance caused by germline mutations in genes involved in telomere regulation results in short and dysfunctional telomeres and clinically in telomere biology disorders (TBDs), rare genetic conditions manifesting as bone marrow failure, liver disease, interstitial lung disease, and increased cancer risk. Chronic inflammation significantly impacts TBDs, potentially exacerbating immune dysfunction and telomere attrition, leading to a vicious cycle of tissue damage. Preliminary studies indicate notable immune dysregulation in TBD patients, including altered T-cell profiles and increased cytokine production. These immune changes may heighten susceptibility to infections and neoplasms, complicating the clinical picture of TBD. We aim to explore how immune dysregulation contributes to chronic inflammation and disease phenotypes in TBD. We hypothesize that an abnormal immune system and altered microbiota create a pro-inflammatory environment, leading to organ damage. For this, we will use two different approaches; first, using telomerase knockout murine models to examine pathways involved in immune dysregulation using sequencing. Second, TBD patient samples will be analyzed by profiling the immune cell populations, measuring cytokine levels, and characterizing microbiota composition, correlating these findings with clinical data to understand their relationship with disease severity.