Current PhD vacancies

Biochemistry & Biophysics Drug targets & drug development Neuroscience Wet lab

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Monoaminergic neurotransmitters act at their cognate receptors and mediate synaptic transmission. Organic cation transporter 3 (OCT3) is part of neurotransmitter-removing transporters that actively end synaptic transmission by removing the neurotransmitters from the synapse. Knowledge about phosphorylation of OCT3 is scarce, direct phosphorylation has not been shown and evidence for the importance of its regulatory function is enigmatic. The aim of the PhD project is to establish knowledge about the structure-function relationship in OCT3 wild type in relation to its phosphorylation status. Overall, we attempt to improve our understanding of the function of OCT3 and how it is controlled by phosphorylation, we aim to i) identify kinase/phosphatase-specific phosphorylation sites in OCT3 and their implication in regulating OCT3 transport function, ii) study the effects of phosphorylation on the pharmacodynamics and pharmacokinetics of OCT3 from human genetic variants and TKIs, respectively, and iii) to establish a plausible hypothesis of the observed effects in relationship to the structural context.

The methods build on a combination of experimental in vitro, microscopical and computational approaches, which are iteratively used for hypothesis generation, refinement and testing. Experimental in vitro approaches will mainly employ biochemical tracer flux experiments and mass spectrometry. Several microscopical methods (confocal, total internal reflection (TIRF) and fluorescence resonance energy transfer (FRET) microscopy) will be applied: TIRF microscopy will be used to assess the distribution of the transporters within the cells as well as on the cell surface; FRET microscopy will ascertain OCT3’s quaternary arrangement at the cell surface.

Animal research Endocrinology and Metabolism Immunology

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The human gut is colonized by trillions of microbes that aid in digestion, modulate immune responses, and generate a variety of products that result from microbial metabolic activities. These products together with host-bacteria interactions influence both normal physiology and disease susceptibility. Importantly, as a result of intestinal leakiness, translocating products from the gut are considered as major contributors to the onset and progression of steatotic liver diseases (SLD). While alterations in the composition and number of intestinal bacteria, known as dysbiosis, is implicated in SLD, the underlying mechanisms by which dysbiosis influences disease progression are not fully understood. In our lab, we aim to dissect how diet-induced dysbiosis affects host immunity in the gut, thereby shaping hepatic inflammation during SLD progression. Using cutting-edge approaches such as single-cell RNA sequencing, specific murine models and human samples, the goal is to characterize the interaction between microbiota and mucosal host immunity during SLD. Particularly, based on our preliminary data, the project will focus on i) antibody-producing B cells as critical node in microbiota-host immunity, and ii) the functional consequences of altered systemic and intestinal immunoglobulin concentrations to steatohepatitis. This research will give critical novel insights in the underlying pathology of SLD and provide a novel basis for the development of new therapeutic strategies. Our background in liver disease research together with a clinical collaboration network sets the stage for fundamental advancements of our understanding of the relevant molecular networks during SLD and associated complications such as atherosclerosis.

Animal research Human research Immunology

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Many myeloid cells are able to form bone degrading osteoclasts (OCs) in vitro. It is important to understand, however, whether this actually is the case in health and disease. In this project, we aim to understand the role of dendritic cells as osteoclast precursors in bone homeostasis and osteoclast driven diseases. Preliminary data showed that myeloid DCs are able to form OCs in vitro as well as in vivo in mice and humans. Importantly, DCs contribute to OC generation without external stimulation or manipulation, suggesting they are pivotal OC precursors in bone homeostasis. Understanding whether all myeloid DCs, or only subpopulations are potent OC precursors will a focus of this project. In addition, we want to analyze, whether there are different OC precursors in bone homeostasis compared to osteoclast driven pathologies such as arthritis or osteoporosis. Using different fate reporter mice marking distinct myeloid and DC populations, in combination with sequencing techniques (single cell RNA-Seq, bulk Seq) we will define osteoclast precursor populations, which we will analyze functionally in subsequent assays. These findings will then be intersected with human data, where preliminary experiments demonstrate an excellent capacity of myeloid DCs to differentiate into bone resorbing OCs. Our large outpatient clinics will allow to determine the distribution of novel OC precursors in patients suffering from inflammatory arthritis and to correlate them with the extent of osteoclast-mediated bone loss. The anticipated results possibly reshape our understanding of osteoclast generation and possibly opens new avenues for targeted interventions in OC-mediated diseases.

Animal research Immunology Molecular and cell biology Wet lab

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Alveolar macrophages (AM), the main innate immune cell population in the lung, are important sentinels of infection, mediate protective inflammation and at the same time are key to restore homeostasis after lung injury. We have found that AM inflammatory responses are fluctuating in a day-time dependent manner. Particularly IL-6 production by AMs seems to be controlled by the circadian clock via a mechanism that involves RNA editing, an important post-transcriptional regulatory layer of gene expression. In this PhD project, we will use established AM ex-vivo culture and murine models of COVID-19 and pneumococcal pneumonia, to further dissect the mechanistic basis for circadian-time dependency of AM responses and how this impacts lung physiology and pathology in situations of stress.

As a PhD student in the Knapp lab, you will be closely supervised and professionally trained in a highly intellectual and diverse environment, which will allow you to identify and foster your personal strengths and interests. If you are interested to do exciting basic lung research in a highly professional and open-minded team, in one of the most livable cities in the world, we are very much looking forward to your application and excited about meeting you soon in person.

Animal research Cardiovascular systems Drug targets & drug development Molecular and cell biology Wet lab

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In the lab of Osmanagic-Myers there is an open PhD position funded for 3 years by Austrian Science Funds. Our group is associated with the Center for Pathobiochemistry and Genetics (Head. Prof. Hengstschläger) that offers a stimulating scientific environment using state-of-the-art technology and individually tailored training.

Project description With increasingly older populations in modern society age is becoming a major risk factor for development of cardiovascular disease and osteoporosis. Endothelial aging (senescence) emerges as a key driver of age-related diseases. This project focuses on the mechanisms of endothelial aging (senescence) in age-related cardiovascular- and bone disease with an aim to develop successful senotherapeutic intervention strategies. We use different premature aging progeria models that recapitulate major features of accelerated cardiovascular and bone aging. The PhD student will be involved in pre-clinical studies as well as employ different molecular biology techniques such as immunofluorescence microscopy, histology techniques, gene expression- and transcriptome analyses, genetic manipulations (e.g.CRISPR/Cas-9) in different iPSC-derived model systems.

Animal research Cardiovascular systems Immunology Wet lab

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Atherosclerosis is a pathology of arterial blood vessels leading to heart attacks and strokes – the major causes of death worldwide. Lipid oxidation products are key mediators in the development of atherosclerosis as well as myocardial infarction. However, the molecular carriers of these lipid oxidation products are poorly characterized. Recent discoveries in our laboratory identified extracellular vesicles as major carriers of lipid oxidation products at the interface with innate immunity. The aim of this project is the characterization of the molecular cargo and of the deleterious effects of extracellular vesicles carrying lipid oxidation products using omics approaches and established preclinical models.

This PhD position is Co-supervised by Taras Afonyushkin

Biochemistry & Biophysics Computer lab Drug targets & drug development Molecular and cell biology Neuroscience

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In this project you will use a broad spectrum of computational approaches to investigate the function of the Organic Cation Transporter 3 (OCT3) to understand how the transporter works, how it recognizes and transports substrates across cellular membranes as well as how OCT3 is regulated by phosphorylation and by lipids. OCT3 belongs to the solute carrier 22 (SLC22) family of membrane transporters. We recently solved its structure (doi: 10.1038/s41467-022-34284-8). In addition, very recently several structures of the related transporters OCT1 and OCT2 became available. This is therefore the perfect moment for using high resolution methods to investigate transporter dynamics to understand its function at the molecular level. OCT3 is a polyspecific transporter for small organic cations, including monoamines, drugs, toxins and chemicals. OCT3 has a broad tissue distribution and plays an important role in the central nervous system. In the brain, OCT3 is associated with clearance of the neurotransmitters dopamine, serotonin and noradrenaline from the synaptic cleft that separates neurons by serving as a low-affinity, high-capacity transporter. As a polyspecific transporter, OCT3 also plays an important role in absorption, tissue distribution and excretion of medication.Interested? You will uncover, at the atomic resolution, transporter function as well as the crucial interactions that are the basis of the structure-function relationship of ligands. You will be using several computational approaches, including modelling, docking, MD simulations and free energy calculations to characterize dynamics, forces and free energy profiles.

Biochemistry & Biophysics Bioinformatics & machine learning Biomedical engineering Medical physics

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This FWF-funded project has the goal to optimize magnetization transfer (MT) MRI technique for non-invasive measurement of myelin content in brains with demyelinating disorder multiple sclerosis. The diagnostic and prognostic information obtained by this myelin-sensitive method will then be compared to our established MRI techniques including state-of-the-art metabolic imaging to evalute clinical value and complementarity of MT. This thesis will involve MR method optimization, data acquisition/evaluation, and analysis of multi-parametric MRI data obtained at our 7T MR scanner in phantoms, healthy volunteers and patients.

Bioinformatics & machine learning Biomedical engineering Cancer Computer lab Mathematics & statistics Medical physics

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Two vacant PhD positions will be focusing on the method development (help establishing a whole body MRI setup or the image acquisition/reconstruction) in a large ERC-funded project (GLUCO-SCAN). The targeted scientific breakthrough of GLUCO-SCAN is the development and evaluation of a non-invasive, radiation-free molecular imaging technology to scan the human body in vivo. It will be based on a new MRI concept: whole-body deuterium metabolic imaging. Deuterium is a simple chemical procedure to artificially label a broad range of molecules, e.g., glucose. In the human body this labeled glucose is metabolized in cells and transferred to al metabolic products, which can be imaged via this new MRI technology and used in a range of major diseases such as cancer.

Animal research Human research Molecular and cell biology

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The capacity of Retinoic Acid Receptor (RAR) and Vitamin-D-Rezeptor (VDR) ligands to prevent Prostate Cancer (PCa) growth and metastasis and their interaction with other nuclear receptors and their respective ligands: The activity of RAR antagonists is best characterised in PCa. The interactions between RAR and other nuclear receptors in PCa, and their possible synergy for a treatment, are however completely unknown. The objective is thus to investigate whether by interfering with the unexplored thyroid receptor (TRβ) / androgen receptor (AR) /RARg/VDR axis, a novel combination approach for therapies in advanced PCa to eradicate CSCs and their progeny can be introduced. Thyroid hormones can stimulate PCa growth and regulate PCa-specific genes autonomously via TRβ or in conjunction with the AR and/or RXRg. Thus, DC-MUV-2 will study the impact of thyroid hormones on tumour growth using faithful models of extensively characterized PCa models. The detailed role of TRβ will be analysed in human PCa cell lines PCa LnCAP, 22Rv1, DU-145, and PC3 and in 3D mouse PCa organoid models by knockout strategies in vitro and in vivo. Transcriptional activity of the TRβ/AR or TRβ/RAR complex will be tested by analysis of gene promoter activity, nuclear translocation of the respective complexes, and gene expression studies. Tumour growth will be comparatively monitored with and without hypothyroidism in PCa xenograft models in vivo. DC-MUV-2 will then study the effects of anti-thyroid hormone agents with or without anti-AR or RAR and/or VDR ligand compounds in vitro and validate the results in PCa xenograft models. Molecular results will be validated with histopathological analyses in an extensive retrospective cohort of FFPE PCa patient samples to identify patient characteristics that may predict response to thyroid hormone therapy. Results from xenograft models will be analysed with histoplasmonics and forwarded to DC-TG for method development. RNASeq and ChiPSeq analyses will be fed to DC-UoB. Results from new hybrid compounds will be fed back to DC-MUW for structure optimisation.

Bioinformatics & machine learning Computer lab Mathematics & statistics Neuroscience

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Neuroscience and machine learning are at the cusp of a transformative era. In neuroscience, we can now record from tens of thousands of individual neurons in multiple brain regions using the new-generation Neuropixels probes and calcium imaging. These large-scale recordings promise new insights into how the activity of individual neurons contributes to healthy and pathological cognitive function. However, to reveal this link, we need new machine learning tools to extract fine-grained information from these complex neural dynamical systems. The new understanding we can derive using these tools can, in turn, inspire new machine learning theories that deal with tasks more like the brain.

Project description: The successful candidate will work on cutting-edge single-neuron recordings in mice and macaques to study how complex cognitive function is distributed across the brain, challenging the current anatomically compartmentalised viewpoint. Under the mentorship of Dr. Adam Gosztolai, you will develop state-of-the-art methods combining geometric deep learning and dynamical systems theory and make new contributions to neuroscience and AI.

Opportunities: The project offers several opportunities for collaboration and developing transferrable skills.

• Build collaborations with neuroscientists and clinicians at the Medical University of Vienna on projects encompassing neuroimaging and brain-machine interfaces.

• Engage with our international collaborator network at EPFL, MIT and Imperial College London.

• Present your work at international conferences in AI and neuroscience.

Animal research Drug targets & drug development Molecular and cell biology Wet lab

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Membrane transporters in the lung epithelium may control the access of inhaled drugs to their pharmacological target sites in lung tissue. In this project, we will use positron emission tomography (PET) imaging to study in vivo the influence of organic cation transporters (SLC22A1, SLC22A4, SLC22A5) on the intrapulmonary kinetics of two clinically used inhalation drugs (ipratropium bromide and formoterol). The PET experiments will be complemented by in vitro transport studies in lung epithelial cell lines and by ex vivo experiments in the isolated perfused rat lung. PET experiments will be performed at the Medical University of Vienna. The PhD student is expected to spend approximately one year in the lab of our collaboration partner Carsten Ehrhardt at Trinity College Dublin in Dublin (Ireland), where the in vitro and ex vivo experiments will be performed.