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Crosstalk between the aryl hydrocarbon receptor and astrocyte mitochondrial dynamics in multiple sclerosis

Grant number: 19/18858-8
Support type:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): September 01, 2020
Effective date (End): February 28, 2021
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Niels Olsen Saraiva Câmara
Grantee:Bruno Ghirotto Nunes
Supervisor abroad: Francisco Javier Quintana
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Brigham and Women's Hospital (BWH), United States  
Associated to the scholarship:18/23460-0 - Evaluation of the mitochondrial dynamics in astrocytes and its impact on the inflammatory response in experimental autoimmune encephalomyelitis, BP.MS

Abstract

Multiple sclerosis (MS) is an autoimmune disease characterized by a chronic and progressive inflammatory condition in the Central Nervous System (CNS), which results in a process of axonal neurodegeneration, leading to neurological deficiency in patients. Currently, there are several therapies that mitigate the symptoms of the disease, however there is no cure available. Recently, it has been established that astrocytes (glial cells) have a key role in regulating neuronal synapses and inflammatory processes in the CNS, being one of the largest sources of reactive oxygen species when subjected to inflammatory stimuli which is directly related to the regulation of mitochondrial dynamics processes. Mitochondria constantly modify their morphology according to the bioenergetic needs of the cell and alterations in these mechanisms of regulation can participate in inflammatory and neurodegenerative processes. The aryl hydrocarbon receptor (AhR) is an environmental sensor that regulates the immune response by repressing activity of the NF-kappa B transcription factor. During CNS inflammation, AhR dampens degeneration, neurotoxicity and recruitment of inflammatory monocytes to the inflamed region. There are few studies associating AhR and mitochondria, however it has already been described the existence of a mitochondrial AhR, localized within the inner membrane space in the organelle, whose function is still unclear. In addition, one study demonstrated that the AhR interacts with a subunit of the ATP synthase complex, suggesting that it may play a significant role in modulating oxidative phosphorylation, which is yet to be determined. This work aims to evaluate the crosstalk between AhR andmitochondrial dynamics and function in astrocytes during neuroinflammation. To accomplish this, mice with conditional knockout of the AhR in Astrocytes (GFAPcre/AhR loxP) will be first used to obtain primary astrocytes cultures, which will be activated with proinflammatory stimuli (ex vivo) and to induce Experimental Autoimmune Encephalomyelitis (in vivo), aiming to analyze how AhR depletion may impact the mitochondrial dynamics and metabolism in a context of inflammation. We hypothesize that AhR may upregulate mitochondrial fusion in astrocytes, reducing their proinflammatory phenotype. A deep investigation on how AhR impacts mitochondrial dynamics has not been performed and should make a huge impact in the field, especially trying to understand how these interactions may play a role in the progression of autoimmune diseases such MS, aiming to develop novel therapeutic strategies. (AU)

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