Doctoral Projects 2018
Doctoral projects offered by LSM faculty members to applicants for 2018:
- You have to apply with our online application tool.
- The deadline to submit your application is the 29th of November 2017, 12:00 CET.
- Please inform your referees as soon as possible to get their affirmation to write a recommendation on your behalf, the deadline for the letters of reference is the 6th of December 2017, 12:00 CET.
- Please click on the name of the supervisor to get redirected automatically to further information on the research group and the scientific contents.
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. Kirsten JUNG (Microbiology, Cell Biology, Biochemistry)
Title : The role of the pyruvate-responsive BtsS/BtsR system in Escherichia coli, Salmonella typhimurium and other enteric bacteria.
Experience and expertise in microbiological, molecular and bioinformatic techniques as well as a strong interest for systemic, e.g. methylomes studies are required.
Behr, S., Kristoficova, I., Wittig, M., Breland, E.J., Eberly, A.R., Sachs, C., Schmitt-Kopplin, P., Hadjifrangiskou, M., Jung, K. (2017) Identification of a high-affinity pyruvate receptor in Escherichia coli, Sci. Rep., 7: 1388.
Supervisor: PD. Dr Stylianos Mickalakis (Epigenetics, Gene Therapy)
Project 1: (Gene Therapy)
Title: Novel gene therapy approaches for inherited eye diseases.
Scientific background. The group works on the development of recombinant adeno-associated virus (AAV) vector-based gene therapies for eye diseases and is part of the RD-CURE consortium that successfully initiated the first ocular gene therapy trial on CNGA3-linked achromatopsia and currently prepares for the initiation of the first German retinitis pigmentosa gene therapy trial. AAV vectors have become the “gold standard” gene delivery tool for targeting retinal cells. AAV-based vectors have been tested in a number of human clinical trials and have proven safe for the use in the human eye. However, there is still unmet need for improvement of the AAV vector platform regarding tropism and transduction efficiency.
Specific aims and methodology. The overarching goal of this project is the development of novel optimized AAV vector-based gene therapy vectors for gene-specific and/or gene independent treatment approaches. The novel vectors will be further developed for optimized efficacy in relevant animal models of inherited blinding diseases. The methodology will include state-of-the-art in vitro and in vivo biochemical, genetic, cell biological and viral gene transfer methods in relevant mouse models. Potential candidates should have a strong interest and background in mouse physiology and anatomy (focus on the eye), molecular biology and gene therapy.
Further information and selected literature:
R. Mühlfriedel, N. Tanimoto, C. Schön, V. Sothilingam, M. Garcia Garrido, S. C. Beck, G. Huber, M. Biel, M. W. Seeliger, S. Michalakis, Front Neurosci 2017, 11, 292.
S. Koch, V. Sothilingam, M. Garcia Garrido, N. Tanimoto, E. Becirovic, F. Koch, C. Seide, S. C. Beck, M. W. Seeliger, M. Biel, R. Mühlfriedel, S. Michalakis, Hum Mol Genet 2012, 21, 4486-4496.
S. Michalakis, R. Mühlfriedel, N. Tanimoto, V. Krishnamoorthy, S. Koch, M. D. Fischer, E. Becirovic, L. Bai, G. Huber, S. C. Beck, E. Fahl, H. Büning, F. Paquet-Durand, X. Zong, T. Gollisch, M. Biel, M. W. Seeliger, Mol Ther 2010, 18, 2057-2063
Project 2 (Epigenetics)
Title: Role of TET-mediated 5mC oxidation for neuronal differentiation and plasticity.
Scientific background. Neuronal networks show a remarkable degree of plasticity during physiological and pathophysiological processes. This plasticity goes along with major adjustments in the expression of key genes. The mechanisms controlling gene expression and neuronal plasticity are not well understood, but it is suggested that epigenetic mechanisms such as DNA methylation contribute crucially to these biological processes. Methylation of the DNA base cytosine is catalyzed by DNA methyltransferases (DNMT) and occurs at the C-5 position of the cytosine base resulting in 5-methylcytosine (5mC). Removal of the methyl group involves oxidation by TET methylcytosine dioxygenases. The overarching goal of this project is to help improving our understanding on how TET enzymes and 5mC oxidation products shape the epigenome of neurons and influence CNS function.
Specific aims and methodology. The functional significance of TET proteins and their enzymatic products in the CNS has not been characterized and will be addressed in this project with specific genetic mouse and cellular models. TET enzymes act in concert with chromatin remodeling proteins and transcription factors. We identified intriguing novel TET interaction partners in mouse retina and induced pluripotent stem cell (iPSC)-derived bipolar neurons. The potential of these proteins to engage with TET3 and modulate its enzymatic activity will be assessed in this proposal. The methodology will include state-of-the-art in vitro and in vivo biochemical, genetic, cell biological and viral gene transfer methods in relevant mouse models. Potential candidates should have a strong interest and background in neurobiology, molecular biology and epigenetics.
Further information and selected literature.:
M. Wagner, J. Steinbacher, T. F. Kraus, S. Michalakis, B. Hackner, T. Pfaffeneder, A. Perera, M. Müller, A. Giese, H. A. Kretzschmar, T. Carell, Angew Chem Int Ed 2015, 54, 12511-12514.
A. Perera, D. Eisen, M. Wagner, S. K. Laube, A. F. Künzel, S. Koch, J. Steinbacher, E. Schulze, V. Splith, N. Mittermeier, M. Müller, M. Biel, T. Carell, S. Michalakis, Cell Rep 2015, 11, 283-294.
T. Pfaffeneder, F. Spada, M. Wagner, C. Brandmayr, S. K. Laube, D. Eisen, M. Truss, J. Steinbacher, B. Hackner, O. Kotljarova, D. Schuermann, S. Michalakis, O. Kosmatchev, S. Schiesser, B. Steigenberger, N. Raddaoui, G. Kashiwazaki, U. Müller, C. G. Spruijt, M. Vermeulen, H. Leonhardt, P. Schar, M. Müller, T. Carell, Nat Chem Biol 2014, 10, 574-581
Supervisor: Prof. Dr. Christof Osman (Developmental Biology, Genetics, Biochemistry)
Title: Identification of the molecular machineries responsible for maintenance and inheritance of mitochondrial DNA.
Our lab is interested in the fundamental but poorly understood question of how cells maintain and correctly organize their mitochondrial genomes. Since the mitochondrial genome is essential for energy production in cells, failure in the maintenance of a functional mitochondrial genome has dire consequences that can lead to diseases or aging. Elucidation of the mechanisms that ensure maintenance and organization of error-free mitochondrial genomes therefore holds the key to understand the cause for such diseases or aging phenotypes.
The aim of this project is the identification and functional characterization of proteins required for faithful maintenance and inheritance of the mitochondrial genome. For this purpose, state-of-the-art biochemical, genetic and (super resolution) microscopy approaches will be used.
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.
Supervisor: Prof. Dr. Susanne Renner (Evolutionary Botany, Climate change and Plant Functional Traits)
Title: Climate change and the ecology (two positions are available)
Two doctoral positions (three years) in Evolutionary Botany are available to work on Climate change and plant functional traits.
Skills that will be acquired within this project include field work (especially controlled experiments), physiological measurements (photosynthetic activity, chlorophyll breakdown, chemistry of colour change), programming in R, statistical analysis and models, phylogenetic-comparative analyses; modern research communication.
Exceptionally, for these two projects:
Minimum requirement for these rojects is a MSc with a focus in ecology or evolutionary biology is required. Please email your letter of application, CV, university transcripts (where applicable), and the names of two people who could write a letter of support to Professor Susanne Renner (firstname.lastname@example.org). Evaluation of applicants will begin immediately and continue until the position is filled. Application via the portal also required if you intend to take part in the LSM programme!
For further information click here.