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Interface among DNA repair, metabolism and the inflammatory immune response

Grant number: 21/03182-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2021
Effective date (End): April 30, 2023
Field of knowledge:Biological Sciences - Immunology
Cooperation agreement: Netherlands Organisation for Scientific Research (NWO)
Principal researcher:Niels Olsen Saraiva Câmara
Grantee:Paulo José Basso
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg), AP.TEM

Abstract

The acute kidney injury (AKI) is one of the major public health problems in the world. In South America, the incidence of AKI is 31%, while in Brazil AKI corresponds to 5% of total number of hospitalizations and 30% of Intensive Care Unit (ICU) admissions. One of the causes of AKI is the ischemia and reperfusion injury (IRI), which is induced by impairment in the delivery of oxygen and nutrients, and by the accumulation of toxic products in the kidneys. This imbalance leads to injury of epithelial cells and consequently necrosis- or apoptosis-induced cell death. Apoptosis and necrosis produce reactive oxygen species (ROS) that can cause deleterious effects on the neighboring cells, including DNA damage, in which can also modify the structures of the DNA, besides generating breaks in the mitochondrial and nuclear DNA. To ensure DNA integrity, DNA repair systems are activated by the cells. Nucleotide excision repair (NER) and base excision repair (BER) are the major DNA repair systems related to oxidative DNA damages. Defects in the NER pathway are associated with human hereditary diseases such as Xeroderma Pigmentosum (XP) and patients with XP have impaired cellular immune response. DNA damage has been shown to modulate the T cell immune response by modulating the production of pro- and anti-inflammatory cytokines. Since it has also been demonstrated that ROS modulate the metabolism of activated T cells, we hypothesized that ROS-induced DNA damage influences the T cell metabolism and, consequently, the impaired T cell response seen in IRI. For this purpose, we will use transgenic mice with deletion of XPA and XPC genes, as well as evaluate both metabolic and functional aspects of T cells, gene and protein expression, and kidney tissue morphometry to attend our objectives. The IRI will be induced by bilateral clamping of kidney pedicles. Here, we expect to demonstrate that in the absence of DNA repair mechanisms, the inflammatory response is exacerbated and, therefore, the outcome of the kidney injury will be worse. We believe that part of this impaired inflammatory response is caused by changes in the cellular function, thus connecting the DNA repair mechanisms to the classical metabolic pathways that coordinate cell responses. (AU)

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