By resolution of the Directorate General for Science and Research of the Department of Innovation, Universities, Science and Digital Society of the Generalitat Valenciana, the Grant for Research Groups of Excellence - Prometeo Programme, CIPROM2021/082 has been awarded with the title: Molecular mechanisms of the neurological (cognitive and motor) alterations in hyperammonemia and hepatic encephalopathy. Therapeutic implications.
The grant has been awarded to the Fundación CV Centro de Investigación Príncipe Felipe (CIPF) and the project involves researchers from the CIPF, the INCLIVA Foundation, the Institute of Agrochemistry and Food Technology (IATA) of the CSIC and the Department of Psychobiology of the University of Valencia.
Within the framework of this grant CIPROM2021/082, a post-doctoral contract is announced as detailed below. The contract will be carried out at the CIPF and the person hired will develop his/her research work in the Neurobiology laboratory of the CIPF.
Responsibilities:Characterize the peripheral inflammation induced by chronic hyperammonemia and identify the underlying mechanisms: characterize changes in the immunophenotype and in the blood cytokines profile.Analyze the mechanisms by which peripheral alterations are transmitted to the brain in rats with chronic hyperammonemia and MHE: Analyze the infiltration of immune cells in different areas of the brain and the underlying mechanisms: role of different chemokines and blood-brain barrier permeabilization.Analyze the role of activation by peripheral cytokines (TNFa, IL-1b, IL-6, IL-17) of their receptors on endothelial cells in the induction of neuroinflammation.Characterize the features of neuroinflammation and its progression in the cerebellum and hippocampus of rats with chronic hyperammonemia: Identify the mechanisms by which neuroinflammation in the cerebellum alters neurotransmission, causing cognitive and motor impairment.Evaluate whether extracellular vesicles from plasma of patients with minimal hepatic encephalopathy induce neuroinflammation, alterations in neurotransmission, and cognitive and motor impairment when injected into control rats.Evaluate treatments to reverse neuroinflammation, altered neurotransmission, and cognitive and motor impairment in rats with chronic hyperammonemia and MHE. Analyze the effects of anti-IL-17, bicuculline and extracellular vesicles from Lactobacillus casei.Analyze whether there are differences according to sex in male and female rats in cognitive and motor function, neuroinflammation, glutamatergic and GABAergic neurotransmission and in the effects of chronic hyperammonemia on these parameters. Some of the tasks to be carried out in the framework of these studies are:Isolation and characterization of extracellular vesicles of different origins. Evaluation of its effects in vivo on neuroinflammation, alterations in neurotransmission and cognitive and motor impairment in rats. Characterization of ex vivo molecular mechanisms in cerebellar and hippocampal slices.Perform ex vivo experiments in slices from the cerebellum and hippocampus: obtaining sections using a vibratome or chopper and incubation in a perfusion system with the different treatments to be evaluated.Analyze activation of microglia and astrocytes by immunohistochemistry.Quantification of the content of inflammatory markers in specific regions of the cerebellum and hippocampus using immunohistochemistry and immunofluorescence.RNA extraction from tissue and cell samples.Analyze inflammation markers using quantitative PCR.Analysis of protein content by Western blot and ELISA assays.Evaluate the membrane expression of neurotransmitter receptors and receptors. Determination of ammonia in blood.Evaluation of cognitive and motor function in rats using different behavioral tests: motor coordination test (Beam Walking, Catwalk, Motorater), memory and learning test (Y maze, radial maze, location memory test and recognition of novel object) and other complementary tests to analyze fatigue, itching and thermal sensitivity.Use of programs for statistical analysis and data representation: GraphPad Prism, Excel and SPSS.Preparation of results for presentation in communications at conferences and in scientific articles.
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