2.2. 2023,
Mitochondriální fyziologie
Laboratory name: Mitochondrial Physiology
PhD project:
Extending our discovery of H2O2 (redox) signaling by NADPH oxidase-4 (NOX4) being essential for glucose-stimulated insulin secretion (GSIS), published in Diabetes 2020, we’ll study EndoC-βH1 cells and mitochondrial matrix metabolomics using beta-cell-specificMITO-tag mice for mitochondrial separation. We’ll determine sites and ways of stimulation of superoxide/H2O2 sources of the respiratory chain, dehydrogenases or ETFQOR, study ways of redox signal transfer and main targets of redox signaling, including the one upon branched-chain-ketoacid and fatty-acid-stimulated insulin secretion (FASIS). We’ll distinct between the direct H2O2 diffusion vs. peroxiredoxin-mediated redox relay and verify redox targets (KATP, TRPM2 channels), relative to matrix Ca2+, for GSIS also to PKA or EPAC2 and for FASIS namely to GPR40-receptor and PKC pathways. It will be verified by time-courses of insulin and glycemia in wild-type or NOX4 KO mice upon physiological timing and doses. We’ll join advanced techniques in cell & mol.biology to report in prestigious publications forecasting translation to diabetology.
References:
Plecitá-Hlavatá L, Jabůrek M, Holendová B, Tauber J, Pavluch V, Berková Z, Cahová M, Schröder K, Brandes RP, Siemen D, Ježek P. Glucose-Stimulated Insulin Secretion Fundamentally Requires H2O2 Signaling by NADPH Oxidase 4. Diabetes. 2020 Jul;69(7):1341-1354. doi: 10.2337/db19-1130.
Plecitá-Hlavatá L, Engstová H, Holendova B, Tauber J, Spacek T, Petrásková L, Kren V, Špačková J, Gotvaldová K, Jezek J, Dlasková A, Smolková K, Jezek P. Mitochondrial superoxide production decreases upon glucose-stimulated insulin secretion in pancreatic β-cells due to decreasing mitochondrial matrix NADH/NAD+ ratio. Antioxid Redox Signal. 2020 Oct 20;33(12):789-815. doi: 10.1089/ars.2019.7800.
Ježek P, Holendová B, Jabůrek M, Dlasková A, Plecitá-Hlavatá L. Contribution of Mitochondria to Insulin Secretion by Various Secretagogues. Antioxid Redox Signal. 2022 May;36(13-15):920-952. doi: 10.1089/ars.2021.0113.
Supervisor (email): Petr Ježek, PhD., DSc. (jezek@biomed.cas.cz)
Candidate’s profile (requirements):
We are seeking outstanding self-motivated candidates with master's degree or equivalent in molecular biology, biochemistry, physiology, biophysics, medicine or related fields, or those expecting to obtain their degree this year. Candidates should be fluent in English. Experience with in vivo models (mouse, rat) as well as with in vitro cell cultures and molecular biology techniques are preferential.
