All available projects have been listed. Do not submit your application until you have selected a project list.

Dr. rer. nat. Merly Vogt

Institute for Diabetes and Cancer

Metabolic Programming across Generations (MPaG)

Project Description 

Deciphering the Signals underlying Metabolic Programming of the Nervous System

In light of the rampant global increase of obesity and associated comorbidities across all age groups, metabolic programming – the concept that an adverse nutritional and metabolic environment can exert intergenerational and potentially transgenerational effects on metabolism and health – has gained significant attention. The developing nervous system has emerged as a primary target site for metabolic programming. Animal studies have shown that maternal diet-induced imbalances of metabolic hormones, such as insulin, impact distinct phases of neurocircuit formation across the nervous system. These defects have been associated with aberrant behaviors in offspring of malnourished mothers, ranging from changes in feeding and locomotory behaviors, to impairments in learning and memory. Thus, the nutritional experiences of our ancestors can impact the well-being of future generations far beyond just metabolic health. An in-depth understanding of the underlying mechanisms of metabolic programming could therefore provide a plethora of opportunities to develop effective preventative or therapeutic strategies to interfere not only with the onset and progression of disorders, but also with its “inheritance” to subsequent generations. However, detailed mechanistic insights and proof of causality between observed molecular, cellular, and phenotypical changes necessary to develop such therapies, remain scarce. Due to the complexity of metabolic programming in general, and the mammalian nervous system in particular, we established two paradigms of parental malnutrition, i.e. early life starvation (ELS) and high-fat diet (HFD) in C. elegans – a relatively simple organism that still exhibits a high conservation of signaling pathways regulating metabolism, as well as nervous system development. By employing unbiased transcriptomic and behavioral screens, as well as carefully characterizing changes of neuronal morphology in offspring of ELS and HFD mothers, we have identified a subset of neurons that display functional changes in response to either or both of these aberrant parental dietary experiences. As part of their research program over the summer, the intern will determine which upstream signals are responsible for the observed changes of neuronal function by performing confocal microscopy, behavioral assays and molecular analyses in wildtype and pre-selected mutant offspring of malnourished parents.  The results obtained during this internship will be invaluable for the ongoing success of this project and will provide important insights into how metabolic programming of the nervous system is mediated across generations.

Dr. Anastasia Georgiadi

Institute for Diabetes and Cancer

Endocrine Pharmacology

Project Description:

Investigating adipose tissue diversity using mixed cell organoid cultures

Our research is focusing on molecular mechanisms that support and coordinate adipose tissue remodelling. We are studying brown and white adipose tissue remodelling in the context of cold exposure and high fat diet. We have generated single nuclei signatures of fat remodelling and we study non adipocyte cell types which can influence adipose tissue function. In this internship the candidate will work in adipose tissue organoids aiming to clarify paracrine signalling between adipocytes and endothelial cell populations. The project involves cell culture of mouse primary cells, Seahorse analysis, Western blot and qPCR as well as confocal microscopy.

Dr. Mauricio Berriel Diaz

Institute for Diabetes and Cancer

Division Metabolism and Cancer 

Project Description

Functional Characterization of Tumor-Derived Mediators in Cancer Cachexia 

Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss, reduced muscle strength, and atrophy, driven by metabolic dysregulation and anorexia induced by cancer. This systemic disorder affects multiple organs, significantly impairing the quality of life and prognosis of cancer patients. While significant progress has been made in understanding its pathomechanisms, key aspects remain to be fully elucidated, and effective treatment strategies are still needed. 

Despite the multifactorial nature of cancer cachexia, in which tumor-host metabolic interactions play a key role, tumor-secreted mediators are pivotal in initiating the wasting process. Although some phase II clinical trials target known cachexia mediators, these factors may be central only in a subset of patients, suggesting a certain degree of heterogeneity in the composition of factors driving cachexia development. This underscores the critical need to identify and functionally characterize novel tumor-derived mediators. 

To this end, we employed innovative quantitative secretome analysis method combining click chemistry, pulsed stable isotope amino acid labeling and mass-spectrometry detection. This technology allowed us to selectively enrich and quantify secreted proteins from cell lines under optimal culture conditions (i.e. in the presence of serum), thereby identifying proteins differentially secreted between the well-established cachexia-inducing cell line Colon 26 (C26) and non-inducing MC38 colon carcinoma cells.  

In this project, we aim to test and characterize the role of these candidate proteins in cancer cachexia using in vitro models, with the ultimate goal of identifying new potential mediators of cachexia and therapeutic targets for treatment. 

Specifically, we will: a) characterize the expression and secretion of these proteins across a panel of cancer cell lines; b) perform gain- and loss-of-function experiments, including overexpression in non-cachexia-inducing cells and knockdown in cachexia-inducing cells; and c) investigate their mechanisms of action, potentially using pharmacological approaches to inhibit their function. This strategy will facilitate the pre-selection of potential tumor-derived mediators of cancer cachexia for further in vivo analyses. Ultimately, this approach holds promise for developing targeted treatments to mitigate muscle wasting, thereby alleviating the devastating impact of cancer cachexia and improving clinical outcomes for cancer patients. 

Dr. Siegfried Ussar

Adipocytes & Metabolism (ADM)

Project Description

Functional characterization of aptamers targeting metabolic dysfunction

Targeting cell surface proteins is key for tissue selective drug delivery and many cell surface present interesting pharmacological targets itself. Traditional approaches use small molecules or antibodies to bind to and modulate the function of these proteins. However, development of these molecules is often complex and expensive. In contrast DNA or RNA aptamers, which are single stranded oligonucleotides, can be easily selected in a standard Biology laboratory. Aptamers can bind their target with very high affinity and are significantly smaller than antibodies. Based on the aptamer selection protocols applied in our laboratory we not only select aptamers binding to specific proteins, but we also aim to target protein-protein interactions or certain conformational states of the target proteins to modify their activity. We currently have several aptamers targeting cell surface proteins with important functions in whole body metabolism. 

The main aim of this project is to characterize one or several of these aptamers, with respect to binding affinity, modification of target protein function and tissue distribution of the target protein or epitope. To this end, we will, embedded within our aptamer group, perform immunofluorescence stainings, flow cytometry experiments, as well as biochemical and cell biological studies to determine the modulation of target protein activity upon aptamer binding. Based on these and additional studies within the group, we aim to develop novel aptamer-based drug candidates to prevent or treat metabolic diseases, especially insulin resistance and type 2 diabetes. 

Dr. Prisca Chapouton

Institute of Diabetes and Regeneration Research

Insulin/IGF Signalling

Project Description

Function of the Insulin Inhibitory Receptor (Inceptor) in Proinsulin Processing and Degradation

The maintenance of insulin content and secretory capacity of beta cells of pancreatic islets is crucial for the maintenance of normoglycemia in the body, a process that becomes disrupted under diabetic conditions. Beta cells produce large quantities of the hormone proinsulin, processed to insulin and packaged into secretory granules that are released upon nutrient stimulation. Both proinsulin and secretory granules are subject to quality control and degradation. We have shown that an abundant beta cell transmembrane protein, inceptor, binds to proinsulin and acts on its degradation (Siehler et al., Nature Metabolism,2024).
This project aims at understanding in a precise manner at what step inceptor is involved in maturation and degradation of proinsulin. We will employ biochemical methods and high-resolution microscopy on cell lines that have been generated in our lab to dissect on one hand the time of interaction between inceptor and proinsulin and on the other hand the secretory granules behavior and content.

Tasks:
Cell culture, microscopy, image analysis, biochemical purification of secretory
granules.

Reference:
Siehler J, Bilekova S, et al. Inceptor binds to and directs insulin towards lysosomal degradation in β cells. Nat Metab. 2024 Nov 25. doi: 10.1038/s42255-024-01164-y. Epub ahead of print. PMID: 39587340

Dr. Kenneth Dyar

Institute for Diabetes and Cancer

Metabolic Physiology

Project Description

Entrainment of skeletal muscle circadian clocks by novel exerkines
 

Chronic circadian misalignment, as occurs in shift workers and late chronotypes, increases metabolic disease risk. Exercise promotes health and metabolic homeostasis, in part by entraining and maintaining alignment of circadian clocks in peripheral tissues. While exerciseinduced metabolites and proteins (so-called exerkines) may play a role entraining skeletal muscle clocks, specific mediators and their mechanism(s) of action remain mostly unknown. In this project we aim to test and characterize specific exerkines we recently identified, and systematically explore whether and how they might impact circadian gene and protein expression in cultured muscle cells. Specifically, we will profile 24-hr gene (qPCR) and protein levels (western blot) in cultured myotubes after acute treatment with selected exerkines, while also investigating their impact on muscle cell metabolism using oxygraphy (seahorse) & targeted metabolomics. This project holds promise for developing new therapies to mimic some of the effects of exercise on 
circadian clock regulation.

Dr. Raffaele Teperino

Institute of Experimental Genetics

Environmental Epigenetics

Project Description:

Circulating RNAs as biomarkers of metabolic healt

Project description

Small non-coding RNAs (sncRNAs) are important regulatory molecules of genome function. We have recently discovered that the expression of sncRNAs encoded by the mitochondrial genome (mt-sncRNAs) is induced by an acute dietary intervention in mice in both somatic (Darr et al. Cell Reports 2020) and germ cells, where they also correlate with BMI (Tomar et al. Nature 2024). Preliminary data from human skeletal muscle biopsies further suggest them as markers of responsiveness to lifestyle intervention in obese subjects at high-risk for Type 2 Diabetes (unpublished). The goal of this project is to study mt-sncRNAs expression in human blood and establish them as circulating biomarkers of metabolic health. The intern will learn how to work with blood RNA, build sequencing libraries from smallRNAs, and navigate data analysis and interpretation.