Dissertations
Dissertations
Rowmika Ravi, 31 March 2023
Metabolomics and genomics approach in cardiovascular diseases
What are the key findings or observations of your doctoral research?
The studies show for the first time a comprehensive metabolic signature of simvastatin treatment, SLCO1B1 variant carriers during simvastatin therapy and pathogenic variant carriers of HCM and DCM. We report changes in several novel metabolite concentrations in the individuals on simvastatin treatment indicating that simvastatin exerts profound pleiotropic effects on different metabolite pathways, including lipids, steroids, degradation of branched chain amino acids, disturbances in the gamma-glutamyl cycle, folate, glutamate, and proline metabolism. We further report that simvastatin lowers LDL-cholesterol through several distinct pathways in the carriers of SLCO1B1 c.521C>T variant, including steroid, bile acid, dicarboxylic acid, and glycerophospholipid pathways.
This is also the first study to report that SLCO1B1 c.521C>T variant does not play a role in causing simvastatin-induced diabetes, suggesting a direct role of simvastatin in risk for type 2 diabetes.
Investigation of HCM pathogenic variant carriers indicated that the hypertrophy of cardiac cells is regulated not only by factors predisposing cardiac hypertrophy (left ventricle wall thickening), but also by factors that attempt to counteract hypertrophy. In the carriers of DCM genetic variants, the pathophysiology could be elucidated with identification of a metabolite profile compatible with vascular endothelial dysfunction, decreased antioxidant precursors, increased reactive oxygen species generation, an increase in cardiac remodeling, and an indication of a disturbed collagen metabolism.
More information at the News page.
Juan Miguel Valverde, 14 October 2022
MRI Segmentation with Deep Learning. Application in Rodent Brain Images with Lesions
What are the key findings or observations of your doctoral research?
The segmentations produced with the developed methods were of higher quality than with other methods, and these automatic segmentations were more accurate than the segmentations annotated by an expert, which is important for reproducibility.
More information at the News page.
Rebekka Wittrahm, 7 October 2022
Protective genes and molecular mechanisms in Alzheimer’s disease (link to thesis available later)
What are the key findings or observations of your doctoral research?
We investigated the mechanisms of a recently identified genetic variant called PLCG2 P522R, which protects individuals that carry the variant from AD. In our mouse study, we found that this genetic variant modulates the function of immune cells both in isolated cultured cells, as well as in the mouse brain. Specifically, it promoted functions such as cell survival, inflammation, and phagocytosis. These findings support the idea that certain aspects of inflammation may be beneficial in AD. In the second study, we investigated a protein called MECP2 and its modification at a specific phosphorylation protein site. This is interesting because the phosphorylation of MECP2 at the S423 site is moderately reduced in early stages of AD in human post-mortem brain samples. We found that if MECP2 is not phosphorylated at S423 site, it may support neuronal viability and protect neurons when they are cultured together with activated microglia. In the third study, we investigated the AD protective APP A673T variant, which lowers the production of beta-amyloid. We found that besides beta-amyloid, this variant also reduces another APP cleavage product called sAPPβ in the human cerebrospinal fluid. We found a similar outcome in 2D and 3D cell culture models of AD, showing that this genetic variant effectively protects from the cellular processes relevant for AD pathology.
More information at the News page.
Ratika Sehgal, 23 September 2022
Nutrient-related metabolites in non-alcoholic fatty liver disease
What are the key findings or observations of your doctoral research?
The results of this thesis shed light on the diverse possibilities of how nutrient-related metabolites could contribute to NAFLD pathogenesis and related clinical phenotypes. Specifically, the correlation of serum tryptophan with LDL biology, serum indolepropionic acid (IPA) with liver fibrosis, and liver content of saturated fat with glucose dysregulation highlight the intricate connections between diet, gut, and liver metabolism in humans.
More information at the News page.
Hannah Rostalski, 16 June 2022
What are the key findings or observations of your doctoral research?
As part of my studies, I have identified a new genetic marker that can help to detect this genetic alteration more easily in the future in large population-based data sets. Also, I have found that microglial cells of frontotemporal dementia patients carrying the C9orf72 repeat expansion as compared to non-carriers function differently and show a quite different gene expression profile. To our knowledge, our findings are new and similar findings have not been published so far by any other research group.
More information at the News page.