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Zanaczenie mikroRNA w uszkodzeniu bariery krew-mózg w encefalopatii wątrobowej
Creator: Institutional creator:Instytut Medycyny Doświadczalnej i Klinicznej im. Mirosława Mossakowskiego PAN
Contributor:Zielińska, Magdalena (Promotor)
Place of publishing: Date issued/created: Description:Cykl 4 publikacji; 173 s.: il., wykr., tabl.; 30 cm. ; Bibliografia zawiera 112 pozycji.
Degree name: Level of degree: Degree discipline : Degree grantor:Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN
Type of object: Subject and Keywords:Encefalopatia wątrobowa ; Bariera krew-mózg ; mikroRNA
Abstract:
Hepatic encephalopathy (HE) develops, due to liver damage and represents a significant epidemiological and economic burden affecting approximately 1 million EU citizens. Brain edema is the most severe clinical symptom, which, in most cases of acute and overt chronic HE, leads to patient death. The mechanism of brain edema in HE primarily results from astrocyte swelling; however, the contribution of vascular factors related to the impairment of the blood-brain barrier (BBB) function also seems significant. However, knowledge of BBB dysfunction and HE damage is far from being complete, considering the number of interacting elements. In pathological processes, increasing attention has been paid to the role of single-stranded, non coding RNAs - microRNAs (miRNAs). Therefore, we formulated a hypothesis that the possible cause of the BBB damage in HE is miRNA profile changes that regulate the BBB. The dissertation aimed to analyze the miRNA profile in plasma and brain cortex of rats with simple hyperammonemia and rats with acute liver failure, and to demonstrate the molecular basis of changes in endothelial cells of brain vessels, the main component of the BBB. Experiments were conducted using (1) a rat model of hyperammonemia and a rat model of acute HE, (2) in vitro models, including a rat brain endothelial cell line (RBE4) and primary brain microvascular endothelial cells (PBMEC), and (3) isolated rat brain vessels. Based on the analysis of the miRNA profile in the plasma and brain cortex of the OA rat’s model, 35 and 128, as well as 128 and 345 in TAA altered miRNAs were identified, respectively. Bioinformatic analysis using available tools and information from databases indicated a potential association of 2 altered miRNAs with genes encoding proteins structurally and functionally related to the BBB (occludin, integrin 1β). Morphological assessment of the BBB showed damage involving changes in endothelial cell morphology correlating with increased BBB permeability, at the cellular level, changes in the expression levels of studied proteins were observed, indicating their functional significance. The involvement of identified miRNA-122-5p and miRNA-183-5p in the reduced expression of occludin and integrin 1β in brain endothelial cells was demonstrated. The decreased density of brain microvessels observed in the acute liver failure model suggested disturbances in brain vascularization comparable to that of 12-month-old rats, indicating changes characteristic of normative aging. A custom system for resistance measuring was constructed, implemented, and tested, serving to assess the integrity of cellular BBB models in time. The measurement was more accurate and independent of pH and temperature fluctuations, making the device a suitable tool for toxicity studies of compounds/drugs when evaluating biological barrier functions. This result adds interdisciplinary value to the dissertation. In summary, the research expands our understanding of HE pathomechanism related to BBB damage, particularly endothelial cells. In the context of liver dysfunction, the study highlights the importance of miRNA in liver-brain axis communication. The results provide new insights into the role of miRNAs in regulating BBB function, which may have potential applications in the diagnosis and/or therapy of acute and chronic neurological disorders associated with liver diseases.
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Language: Language of abstract: Rights:Creative Commons Attribution BY 4.0 license
Terms of use:Copyright-protected material. [CC BY 4.0] May be used within the scope specified in Creative Commons Attribution BY 4.0 license, full text available at: ; -
Digitizing institution:Mossakowski Medical Research Institute PAS
Original in:Library of the Mossakowski Medical Research Institute PAS
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