Open Doctoral Positions 2018
Doctoral projects offered by LSM faculty members for 2018:
Supervisor: PD Dr. Dr. Christian GRIMM (Pharmacology, Molecular Biology)
Title: Endolysosomal cation channels in health and disease.
Our group is interested in the analysis of cation channels of the TRP (transient receptor potential) superfamily within the trafficking network of the endolysosomal system. Lysosomes are cell organelles involved in the breakdown of proteins, lipids, and other macromolecules.
Lysosomal dysfunction can result in endolysosomal storage disorders (LSDs) such as mucolipidoses or mucopolysaccharidoses but is also implicated in metabolic diseases, the development of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, retinal diseases
and pigmentation disorders, trace metal deficiencies such as iron deficiency, and even cancer. Highly critical for the proper function of lysosomes, endosomes, and lysosome-related organelles (LROs) is the tight regulation of various fusion and fission processes and the regulation of proton and other cation concentrations within the endolysosomal system (ES). TRPML cation channels (TRPML1, 2 and 3) and Two-pore channels (TPCs) have recently emerged as important regulators of such processes within the ES and appear to be essential for a proper communication between the various endolysosomal vesicles. We use lysosomal patch-clamp techniques, molecular and cell biology techniques as well as knockout mouse models to study the physiological roles and activation mechanisms of these ion channels in-depth.
Chao Y-K, Schludi V, Chen C-C, Butz E, Nguyen, P., Müller, M., Krüger J, Kammerbauer C, Vollmar, A., Berking C, Biel M, Wahl-Schott C Grimm C# (2017) TPC2 polymorphisms associated with a human hair pigmentation phenotype result in gain of channel function by independent mechanisms. PNAS 2017 Sep 18. pii: 201705739. doi: 10.1073/pnas.1705739114. Chen C-C, Butz E, Chao Y-K, Grishchuk Y, Becker L, Heller S, Slaugenhaupt S, Biel M, Wahl-Schott C, Grimm C#: Small molecules for early endosome specific patch-clamping. Cell Chem Biol 24(7):907-916.e4, 2017.
Chen C-C, Chunlei C, Fenske S, Butz E, Chao Y-K, Biel M, Ren D, Wahl-Schott C, Grimm C#: Patch clamp technique to characterize ion channels in individual intact endolysosomes. Nature Protoc 12(8):1639-1658, 2017.
Nguyen P*, Grimm C*, Schneider L, Chao Y-K, Watermann A, Ulrich M, Mayr D, Wahl-Schott C, Biel M, Vollmar AM: Two-pore channel function is crucial for migration of invasive cancer cells. Cancer Res 77:1427-1438, 2017.
Ruas M, Davis LC, Chen C-C, Morgan AJ, Chuang K-T, Walseth TF, Grimm C, Garnham C, Powell T, Biel M, Wahl-Schott C, Parrington J, Galione A:
Endogenous TPCs are essential for NAADP-induced Ca2+ signaling. EMBO J 34:1743-1758, 2015.
Sakurai Y, Kolokoltsov AA, Chen C-C, Tidwell MW, Bauta WE, Klugbauer N, Grimm C, Wahl-Schott C, Biel M, Davey RA: Two pore channels control Ebolavirus host cell entry and are drug targets for disease treatment, Science 347:995-998, 2015.
Chen C-C, Keller M, Hess M, Schiffmann R, Urban N, Wolfgardt A, Schaefer M, Bracher F, Biel M, Wahl-Schott C, Grimm C#: A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV. Nature Commun 5:4681, 2014.
Grimm C, Holdt LM, Chen C-C, Hassan S, Müller C, Jörs S, Cuny H, Kissing S, Schröder B, Butz E, Northoff B, Castonguay J, Luber CA, Moser M, Spahn S, Lüllmann-Rauch R, Fendel C, Klugbauer N, Griesbeck O, Haas A, Mann M, Bracher F, Teupser D, Saftig P, Biel M, Wahl-Schott C: High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nature Commun 5:4699, 2014.
Aneiros E, Cao L, Papakosta M, Stevens EB, Phillips SC, Grimm C#:
Biophysical and molecular basis of TRPV1 proton gating. EMBO J 30:994-1002, 2011.
Grimm C, Jörs S, Saldanha SA, Obukhov AG, Pan B, Oshima K, Cuajungco MP, Chase P, Hodder P, Heller S: Small molecule activators of TRPML3.
Cell Chem Biol 17:135-148, 2010.
Grimm C, Cuajungco MP, van Aken AFJ, Schnee M, Jörs S, Kros CJ, Ricci AJ, Heller S: A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. PNAS 104:19583-19588, 2007.
* authors contributed equally; # corresponding or shared corresponding author
Supervisor: Prof. Dr. Martin Parniske (Genetics, Plant biology)
Title: Molecular inventions underlying the evolution of the nitrogen-fixing root nodule symbiosis.
Crop production worldwide is sustained through nitrogen fertilizer produced via the energy-demanding Haber-Bosch process. One group of closely related plants evolved to become independent of nitrogen from the soil by engaging in symbiosis with bacteria that convert atmospheric nitrogen to plant-usable ammonium and are hosted within specialized organs, the root nodules. Nodulation evolved several times independently but exclusively in four related orders, the Fabales, Fagales, Cucurbitales and Rosales (FaFaCuRo) based on a putative genetic predisposition to evolve root nodules acquired by a common ancestor of this clade.
The PhD project will contribute to a larger ongoing effort of the Parniske lab to identify the elusive genetic switches involved in the evolution of nodulation. It builds on the underlying idea that a succession of events co-opted preexisting developmental programs to be activated by symbiotic stimuli. We will systematically investigate and compare the prewired connections between signaling pathways and developmental modules present in non-nodulating and nodulating relatives, to identify components acquired by nodulators. The Rosaceae represent a particularly attractive family to test evolutionary hypotheses by transferring candidate switches from a nodulator into the genome of closely related sister genera to enable nitrogen fixing root nodule symbiosis. Most genera of the Rosaceae including economically valuable targets such as apple and strawberry are non-nodulating. A minority of Rosaceae form ancestral, lateral root related actinorhiza nodules with Frankia actinobacteria, which differs from the derived, more complex symbiosis of legumes with rhizobia. Frankia strains have a very broad host range and can fix nitrogen at ambient oxygen concentrations thus imposing minimal constraints on a host environment suitable for efficient symbiosis. Thus, by retracing small evolutionary steps within the Rosaceae we will take a huge leap towards nitrogen-fertilizer independent crops for sustainable agriculture.