Neuro-pharmacology
Title: Study of the effect of 6-MSITC (Isothiocyanate-wasabi) in the regulation of tauopathies through NRF2 models and its implication in “in vivo” neurodegenerative diseases
Brief summary: NRF2 is a master regulator of cellular homeostasis that regulates the expression of more than 250 cytoprotective genes involved in metabolic reprogramming processes, biotransformation, antioxidant reactions, etc. Under homeostatic conditions, NRF2 is rapidly degraded by KEAP1, which favours its elimination via the proteasome. However, under conditions of oxidative stress, NRF2 escapes this degradation to translocate to the nucleus and favour the expression of its target genes. Pharmacological activation of NRF2 is being pursued by increasing its stability through dissociation with KEAP1. Certain electrophilic compounds are capable of dissociating NRF2 from KEAP1, increasing its activity. Isothiocyanates are classical electrophiles that induce NRF2, by inhibiting KEAP1 at certain cysteine residues. Among them, 6-MSITC, which is a type of isothiocyanate, extracted from Wasabi japonica cruciferous plant. It has been suggested that the consumption of cruciferous plants as a functional food could reduce the risk of neurodegenerative diseases. Given that these plants have a high content of isothiocyanates, the aforementioned neuroprotective effects could be based on the action they have on the transcription factor NRF2. Preliminary results obtained in our laboratory show that 6-MSITC has a strong anti-inflammatory component through the regulation of NRF2, and is capable of reducing the pathological levels of the phosphorylated form of the microtubule-binding protein TAU” in vitro” in hippocampal HT22 cell lines. The pharmacological modulation of the KEAP1/NRF2 union "in vivo" in murine models of Alzheimer's typical of the group by this compound, would be a pharmacological alternative for the study of the activation of NRF2 and its implication in taupacias as in Alzheimer's disease.
Typology: Experimental laboratory work. Basic techniques of biochemistry and molecular biology. Western blots, analysis of gene expression measured by qRT-PCR, cultivation and maintenance of cell lines, manipulation of experimental animals (mice) and necropsies. Isolation and purification of plasmids, cell transfection. Knock-down gene silencing.
Director/s: Antonio Cuadrado Pastor. Professor at the UAM. Email: antonio.cuadrado@uam.es
Angel Juan Garcia Yague. Hired researcher from the UAM. Email: ajgarcia@iib.uam.es
Place of performance: Biomedical Research Institute of Madrid "Alberto Sols". Joint Center CSIC-UAM. Laboratory 1.7.1. Arturo Duperier Street No. 4 28029 Madrid.
Additional information required: the student's ability to compete competitively for applications for national predoctoral scholarships, such as FPU, FPI-UAM, Tatiana de Guzmán el Bueno Foundation scholarships, etc. will be positively valued.