Pharmacology and Toxicology (Grimm)

Department / Institute
Medical Faculty
Subject area
Pharmacology and Toxicology
Project title
Novel endolysosomal transportome/channelome components in health
and disease
Name of supervisor
Prof. Dr. Dr. Christian Grimm
Number of open positions
1
Language requirements
Proficiency in English
Academic requirements
4-year Bachelor's plus Master's Degree; at the time of application, the last final exam should have taken place during the past 4 years.
Project time plan
Full Doctoral Study Model: 36 or 48 months

Project description

Current State of Relevant Research
Cells are the elementary units of all life. Each cell contains numerous organelles that are essential for proper cell function, e.g. ribosomes for RNA into protein translation, a Golgi apparatus for protein modification, or mitochondria for energy production. One organellar machinery that is both essential for intracellular trafficking and degradation but also serves as an important signaling hub is the endolysosomal system. Endolysosomes are key for human health and disruption of endolysosomal function including its central role in intracellular Ca2+ signaling is strongly associated with disease pathology, affecting or causing neurodegenerative and lysosomal storage diseases, cancer and immunological diseases, metabolic, lung, or infectious diseases. The seemingly complex interaction between endolysosomes but also with other organelles raises the fundamental, yet largely unanswered question in cell biology of how a precise regulation of this intracellular communication and interaction network is achieved. Decoding the intracellular signaling pathways governing endolysosomal communication is critical not only for an in-depth understanding of cell biology but also for the many disease pathologies endolysosomal dysfunction is associated with. Aim of this project is to decipher molecular components in mammalian cells that are necessary to tightly coordinate intracellular, in particular endolysosomal transport and communication, postulating that a distinctive set of endolysosomal cation channels/transport proteins are key to these processes. To address this aim, we will apply in vitro and in vivo models, novel techniques in cell biology, subcellular imaging, proteomics, bioinformatics and biophysics (i.e., endolysosomal patch clamp electrophysiology).

Peliminary Work Directly Relating to the Research Program Members of the TRP family of mostly non-selective cation channels, the so called TRPML channels and the related two-pore channels (TPCs) which all reside in endolysosomes have been in depth investigated and characterized in the past. Yet, additional components of the endolysosomal transportome/channelome require further investigation, so do the numerous postulated interaction partners of TPCs and TRPMLs.

Specific Aims
Aims of the projects are 1) to characterize novel interaction partners of TPCs and TRPMLs in endolysosomes using endolysosomal patch-clamp electrophysiology and calcium imaging 2) to characterize additional components of the endolysosomal transportome/channelome 3) to identify novel, currently enigmatic components of the endolysosomal transportome/ channelome

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