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Unrevealing the molecular pathways triggered by the accumulation of intracellular DNA and RNA in diabetic kidney disease patients and mouse models of fibrosis

Grant number: 22/12517-7
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): February 15, 2023
Effective date (End): February 14, 2024
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Niels Olsen Saraiva Câmara
Grantee:Magaiver Andrade Silva
Supervisor: Katalin Susztak
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: University of Pennsylvania, United States  
Associated to the scholarship:20/04592-3 - The role of the intracellular DNA sensor, AIM2, and signaling molecules, STING and MAVS, in proximal tubular epithelial cell metabolism in kidney fibrosis development, BP.PD

Abstract

Persistent, low-grade, sterile inflammation is considered a hallmark of chronic and diabetic kidney disease (CKD and DKD). The critical unresolved question is the actual process that triggers the inflammation, a process intimately linked to all renal DKD and CKD. Nucleic acids, DNA, and RNA, derived from pathogens or the host during cell disturbances are recognized by cytoplasmic sensors and trigger an inflammatory response. Here we propose that cytoplasmic nucleic acid sensors play a key role in kidney disease development. The cytosolic DNA activates the potent, cytosolic nucleotide sensing pathways and triggers the innate immune system, contributing to inflammatory fibrosis and CKD development. DNA accumulation in the cytoplasm in sterile conditions can be the result of mitochondrial damage. In addition, it is suggested that RNA transcripts accumulate in the cytosol due to endogenous retrovirus (ERVs) transcripts expression. In the renal epithelial cell in CKD, the ERVs expression is correlated with the degree of inflammatory fibrosis. Therefore, in this proposal for Research Internship Abroad under the supervision of Profa. Katalin Susztak we aim to deepen our understanding of how the ERVs have accumulated in the kidney and the epigenetic factors that can be associated with its regulation. Moreover, as important as understanding its regulation, studying what cell type and signaling are more prominent in patient's tissue and experimental model CKD will be an important point approach in this proposal. (AU)

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