We offer 1 fully funded PhD position with immediate effect in the PhD program Cellular Basis of Diseases (CBD) at the Medical University of Innsbruck, Austria. The interdisciplinary PhD program addresses the molecular control of metabolism & inflammation and connect basic life science and computational biology with medicine. The duration of a PhD in the CBD program is fixed at four years (eight semesters).

To read more about the program and the requirements, please use the following link:

https://phd-cbdiseases.i-med.ac.at/

The project will be located at the Institute of Cell Biology, Biocenter, Medical University of Innsbruck and supervised by Prof. Lukas Huber (Cell Biology) and Prof. Thomas Müller (Pediatrics).

Project: The role of Seizure threshold 2 (SZT2) in lysosomal signaling and disease

Seizure threshold 2 (SZT2) is a very large and relatively unknown gene that is expressed mainly in the developing and mature brain. The SZT2 protein is 3375 amino acids long and is highly conserved among higher eukaryotes. SZT2 was shown to localize to lysosomes and associate with KPTN, ITFG2, C12orf66 in a quaternary complex called KICSTOR. This complex was shown to negatively regulate mTORC1 signaling in the absence of amino acids. SZT2 depletion prevents formation of the KICSTOR complex and triggers the constitutive localization of mTORC1 to the lysosomal membrane with persistent activation of the pathway, even under nutrient shortage. SZT2 was first identified in 2009 as a gene involved in epileptogenesis, conferring low seizure threshold to KO mice and with a putative role in resistance to oxidative stress. Since then, there have been several cases reporting that mutations in SZT2 are associated with Early infantile epileptic encephalopathy 18, a recessively inherited disease characterized by lack of psychomotoric development, dysmorphic facial features and early onset of refractory seizures. Nonetheless, the mechanism that links SZT2 to epilepsy remains unclear.

CRISPR/Cas9 edited knock out cell lines, patient material and cell lines harboring relevant patient mutations have been generated and are available to study the role of SZT2 and its interaction partners in physiological lysosomal signaling as well as in the context of diseases, such as Early infantile epileptic encephalopathy.

Contact:

Lukas.a.huber@i-med.ac.at and Thomas.mueller@i-med.ac.at
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