ORGANOIDS AS A MODEL FOR STUDYING COMPLEMENT-MEDIATED KIDNEY DISEASES

• Grant number: 24/09605-7
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: November 29, 2024
• End date: November 28, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Karina Thieme
• Grantee: Mariana Charleaux de Ponte
• Supervisor: Tobias Huber
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Universitätsklinikum Hamburg-Eppendorf, Germany
• Associated to the scholarship: 21/12782-0 - TNF-alpha and podocyte dysfunction in diabetic kidney disease, BP.PD

Abstract

The complement system is a conserved part of innate immunity, critical for protecting the body against pathogens, maintaining tissue homeostasis and orchestrating adaptive immune responses. The kidneys are a main target organ for complement induced injury and are also a major source of local complement factor production. It has been shown that not only systemic, but also local and intracellular complement production in the kidney and other organs has crucial functions in immunity and basic cellular metabolism. Recent advances in drug development will soon allow clinical targeting of individual factors of the complement system. To target the drug's bioavailability to complement activity in intracellular, local or systemic compartments and to select up- or downstream targets within the complement system further research is needed. To overcome obstacles of rodent-based studies such as the lack of faithful kidney disease models and immune system differences between mice and men, kidney organoids derived from patient cells offer a personalized medicine approach to decipher the role of the complement system and target treatments in disease. Thus, the objective of the present study is to establish a model based on human kidney organoids for investigating the pathophysiology of complement-mediated kidney diseases. For that, primary urinary cells from urine of healthy donors will be collected and reprogrammed into human pluripotent stem cells (hPSCs). These cells will be subjected to CRISPR/Cas9 technology for creating complement factor knock-out hPSCs, which, in turn, will be used for differentiation into kidney organoids. After differentiation, the cell-specific expression patterns of complement factors in physiological and inflammatory contexts, driven by IL-1B and TNF, will be assessed. Specifically, CFH and C3 complement knock-out states will be assessed for their impact on cellular composition, inflammation and fibrosis. Kidney organoids allow a personalized medicine approach to deciphering diseases and have the potential to advance the field of nephrology by discovering new therapeutic pathways for complement-mediated kidney diseases.