Molekulaarse neurobioloogia uurimisrühm
Uurimisrühma juht
Seotud struktuuriüksus
TalTech prioriteetne teadussuund
Ülevaade
Peamiseks uurimisteemaks on geeniekspressiooni ja signaaliülekande regulatsioon närvisüsteemis ja erinevates haigustes. Uuritakse transkriptsiooni, mRNA ja valkude rakusisese lokalisatsiooni, translatsiooni, posttranslatsiooniliste modifikatsioonide ja signaaliülekande molekulaarseid aluseid. Spetsiifiliselt uuritakse: (1) Molekulaarseid mehhanisme, mis kontrollivad neurotrofiin BDNFi transkriptsiooni ja translatsiooni. (2) Aluselise heeliks-ling-heeliks transkriptsioonifaktori TCF4 funktsioone imetajate ja Drosophila närvisüsteemis ja regulatsiooni häireid Pitt-Hopkinsi sündroomis ja skisofreenias. (3) Erinevate haiguste varajase diagnostika molekulaarseid markereid verest.
Uurimisrühma liige
Endised liikmed
Klassifikaator (Frascati)
Võtmesõna
neurotrofiinid
BDNF
bHLH transkriptsioonitegurid
TCF4/E2-2
neuraalse aktiivsusega reguleeritud transkriptsioon
Pitt-Hopkinsi sündroom
skisofreenia
Covid-19
südame- ja kardiovaskulaarsed haigused
Seotud projektid
Tähtsamad tulemused
2024. aastal jätkus aktiivsusega reguleeritud geeniekspressiooni uurimine närvisüsteemis. Tulemused: 1. Kuigi BDNF geeni transkriptsioonilist regulatsiooni on neuronites põhjalikult uuritud, on BDNF regulatsiooni ja funktsiooni kohta mitte-neuraalsetes rakkudes vähem teada. Aju kõige levinum mitteneuronaalsete rakkude tüüp, astrotsüüdid, ekspresseerivad vastusena katehhoolamiinidele BDNF-i. Uuriti nelja potentsiaalset BDNF geeni enhanseri piirkonda kasutades reportergeenidega teste, CRISPR / Cas9 meetodeid ja CAPTURE-3C sekveneerimist. Saadud tulemuste põhjal järeldati, et BDNF geenist 840 kb ülesvoolu asuv piirkond reguleerib BDNF geeni katehhoolamiinidest sõltuvat ekspressiooni näriliste astrotsüütides. Näidati ka, et seda regulatsiooni vahendavad CREB ja AP1 perekonna transkriptsioonitegurid. See on esimene praegu teadaolev enhanser, mis koordineerib BDNF geeni transkriptsiooni mitte-neuronaalsetes rakkudes (Avarlaid et al., Glia, 2024). 2. BDNF geeni ajalis-ruumilist ekspressiooni neuronites kontrollivad erinevad transkriptsioonitegurid, mis seonduvad nii selle proksimaalsete kui ka distaalsete regulatoorsete piirkondadega. Müotsüütide võimendajafaktori (MEF2) transkriptsioonifaktorite perekond, mis algselt avastati selle rolli tõttu lihaste arengus ja funktsioonis, on oluliseks regulaatoriks ka aju arengu ja neuronite plastilisuse erinevates aspektides. Rühma eesmärk oli uurida MEF2 transkriptsioonitegurite rolli neurotrofiin BDNF geeni reguleerimisel roti ajukoore ja hipokampuse neuronites. Tulemused näitasid, et MEF2 transkriptsiooniteguritest sõltuv enhanser, mis asub -4, 8 kb kaugusel BDNF geenist, reguleerib endogeense BDNF geeni ekspressiooni koekultuuris kasvatatud hipokampuse neuronites. Näidati ka -4,8 kb enhanseri neuraalsest aktiivsusest sõltuvat aktiveerimist in vivo. Kindlatel MEF2 perekonna transkriptsiooniteguritel oli BDNF geeni reguleerimisel unikaalne roll, mis sõltus konkreetsest ajupiirkonnast ja stiimulitest. Kokkuvõttes näidati, et MEF2 perekonna transkriptsioonitegurid on BDNF geeni olulised regulaatorid, mis reguleerivad BDNFi transkriptsiooni nii distaalsete kui ka proksimaalsete regulatoorsete piirkondade kaudu (Avarlaid et al., J. Biol. Chem, 2024).
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// Glia (2024) vol. 72, 1, p. 90-110 : ill.https://doi.org/10.1002/glia.24463 - Avarlaid, A., Falkenberg, K., Lehe, K., Mudo, G., Belluardo, N., Di Liberto, V., Frinchi, M., Tuvikene, J., Timmusk, T. An upstream enhancer and MEF2 transcription factors fine-tune the regulation of the Bdnf gene in cortical and hippocampal neurons // Journal of biological chemistry (2024) vol. 300, 6, art. 107411, 12 p. : ill.
https://doi.org/10.1016/j.jbc.2024.107411