Short introduction of the individual PhD projects

PhD Project 1 [P1]: Advanced cell culture models for lipid metabolic diseases

The Question: Rare and severe metabolic diseases, like LCHADD or VLCADD, lack placebo controlled therapy groups for improving therapeutic standards. In this project we will develop a fully 3D bioprinted fibroblast model to study mitochondrial morphology, function and lipid composition in β-oxidation defects. A perfusable tissue-on-CHIP-system, as recently published (Nothdurfter et al, Biofabrication, 2022) will be used as testing platform for novel therapies.

The Goal: is to use this patient-derived 3D tissue model as standardized screening platform for novel treatments, and to understand how lipid composition impairs mitochondrial function in LCHADD-patients.

Tandem Supervision Team: Judith Hagenbuchner and Katrin Watschinger

https://doi.org/10.1088/1758-5090/ac5fb7

https://doi.org/10.1038/s41598-018-21519-2

PhD Project 2 [P2]: LC-MS/MS inverse problem data analysis approach

The Question: The reliable quantification and identification of lipids in biological samples represents a major challenge on multiple levels. Recently, we have demonstrated that the structural information contained in mass spectrometric lipidomics datasets can be comprehensively exploited by employing a mathematical structural modelling approach. These principles can now be applied to a larger number of lipid classes and their structural variants.

The Goal: We aim to establishing novel analysis strategies of mass spectrometric lipidomic data that allow to characterize complex lipid compositions. For this, we employ a heuristic deconvolution model in combination with other bioinformatic techniques to conduct in-depth characterizations of lipid species. This is key to fully understand the processes that drive membrane lipid damage and their repair in inherited metabolic diseases as well as polygenic conditions.

Tandem Supervision Team: Markus A. Keller and Lukas Neumann

https://doi.org/10.1016/j.celrep.2020.02.115

https://doi.org/10.1073/pnas.1719407115

PhD Project 3 [P3]: Artificial neural network based imaging analysis

The Question: In human cells the identification and segmentation of mitochondrial networks can be complicated. This relatively hard problem has nonetheless attained a large degree of attention recently, because alterations in mitochondrial morphology have been linked with a number of diseases that are related to abnormalities in metabolism (see eg. Hagenbuchner et al, Sci. Rep. 8, 3254 (2018)). It was pointed out that mitochondrial morphology classification in thick cells has to take into account the 3D nature of mitochondrial structures. Still most algorithms use 2D segmentation, and the ones that actually use 3D information often rely on stringent image preparation protocols and random forest algorithms to perform the analysis and classification of the mitochondrial network structure.

The Goal: We will develop a CNN based automated and reproducible workflow for segmentation and classification of images of mitochondrial networks. This will result in an operator-independent tool to quantify network structures, sizes and the amount of defects. Our method can be used to localize oxidative stress and estimate the ROS levels in experiments but also as a diagnostic aid in diseases related to mitochondria morphology (e.g. LCHAD-, VLCAD-deficiency).

Tandem Supervision Team: Lukas Neumann and Judith Hagenbuchner

https://doi.org/10.1038/s41598-018-21519-2

PhD Project 4 [P4]: Membrane lipid peroxidation in GPX4-deficiency

The Question: Inflammatory bowel diseases, such as Crohn’s disease, arise from perturbation of gut epithelial cells, which is poorly understood. Based on previous studies (Mayr L et al Nature communications 2020, Schwärzler J et al Gastroenterology 2022), we hypothesise that a Western style diet perturbs lipid metabolism in epithelial cells from patients with Crohn’s disease, which sets a basis for an inflammatory tone.

The Goal: Delineate how dietary lipids evoke an inflammatory response from gut epithelium

Tandem Supervision Team: Timon E. Adolph and Markus A. Keller

https://doi.org/10.1038/s41467-020-15646-6

https://doi.org/10.1053/j.gastro.2022.01.004

PhD Project 5 [P5]: Role of ether lipids and BH4 in ferroptosis

The Question: Ether lipids, their metabolic enzymes as well as tetrahydrobiopterin and its rate-liming biosynthetic enzyme GCH1 impact on peroxidation of membrane-contained polyunsaturated fatty acids leading to ferroptosis (PMID: 32939090, PMID: 32778843). The precise mechanism is not clear. As ether lipids are enriched in polyunsaturated fatty acids and we have recently identified an important enzyme in ether lipid biosynthesis (PMID: 32209662) we will investigate how the different ether lipid subclasses influence ferroptotic cell death and whether a catabolic enzyme in ether lipid metabolism that depends on tetrahydrobiopterin (PMID: 20643956) might be the crucial player linking both processes.

The Goal: Find out what role the ether lipid enzymes PEDS1 and AGMO play in ferroptosis

Tandem Supervision Team: Katrin Watschinger and Timon E. Adolph

https://doi.org/10.1073/pnas.1917461117