CBMR International PhD and Postdoc Program

Description: Secreted proteins enable cells to communicate with each other and play a vital role in regulating whole body metabolism. Mass spectrometry-based proteomics is an attractive tool for discovering novel secreted proteins, as it allows for the comprehensive analysis of large numbers of proteins. This project aims to discover novel secreted proteins in human body fluids obtained from both healthy individuals and those with type-2 diabetes, before and after an exercise intervention. In addition to identifying novel secreted proteins, this project will also involve characterizing the role of proteins that are regulated under diabetes and exercise conditions. This will be achieved using both in vitro and in vivo model systems, providing a comprehensive understanding of the functions of these proteins and how they are affected by exercise and diabetes. Overall, this project will advance our understanding of inter-organ communication and may provide therapeutic targets to improve metabolic health.

Description: Salt-Inducible Kinases (SIKs) were initially described for their role in sodium sensing but have since been shown to regulate many physiological processes, including metabolism, immune responses, and circadian rhythms. SIKs are activated or inhibited in response to extracellular signals (e.g., hormones) that are cell surface receptor mediated, and regulate multiple targets to reprogram transcriptional and post-transcriptional processes in response. We and others have demonstrated that SIKs regulate metabolic responses (e.g., hepatic gluconeogenesis) to fasting/feeding and thus are implicated in playing a key role in controlling glucose homeostasis. However, the precise mechanism by which SIKs are regulated by fasting/feeding or other extracellular signals at the molecular level is elusive. The major goal of this PhD project is to investigate the molecular mechanism by which SIKs are switched on and off by extracellular signals such as hormones, regulate downstream targets, and ultimately specific transcriptional programs metabolic processes, including gluconeogenesis. The project takes multidisciplinary approaches involving structural biology, biochemistry and in vivo physiology using state of the art methods/technology.

Description: Technological platforms – such as single-cell omics, metabolomics, and computational chemistry – are a main feature of CBMR. They are advanced technologies that are both sites of active scientific investigation and technologies that are well-understood enough to be applied across many different areas of investigation. From the point of view of philosophy of science, they may be seen to occupy an intermediate position between experimental objects and technological systems.

The project will investigate this in-between role of technological platforms as well as how they mediate between different groups, disciplines and research questions. Being advanced technologies, the platforms are not integrated in each group separately, but become material connections across the center. The project will thus consider both the scientific and conceptual challenges of standardizing results and the social connections established.

Methodologically the project will mix ethnographic methods of observation or interview within CBMR with conceptual work drawing on philosophy of science in practice, STS or history of science.

Description: This project focuses on the contemporary and historical role of research-led museums like Medical Museion. How do they link the ‘ivory tower’ of academic research to the public realm of a cultural venue? How can such an institution most effectively involve and listen to interest groups and the general public? And finally, how is this sort of work done similarly, but differently in other international contexts.

The investigation picks up on a significant recent trend in museum thinking that focuses on the accessibility and diversity of their outputs and outcomes, which here will focus on exercising those participatory principles in museum workshops and displays that work with the science as well as the social/cultural contexts of cardiometabolic medicine. Specifically, the project will investigate novel forms of stakeholder engagement being developed at Medical Museion, following how that stakeholder-focused work can be planted in experimental displays and events presented to the public. It will also involve comparison and collaboration with similar initiatives being undertaken in other international organizations, providing a paradigmatic case study.

Moving through a series of stages (1 - mapping the context, history, and theory of such practices; 2 - establishing a network of institutions; 3 - developing and studying specific projects, and 4 - sharing insights across an international network), its findings will be shared through papers, workshops, and a conference.

Description: The project seeks to overcome the challenge of transforming early-stage projects into valuable assets by conducting effective target validation studies. Its main objective is to validate the physiological role of the G protein-coupled receptor 39 (GPR39) in obesity, diabetes, and Non-Alcoholic Fatty Liver Disease (NAFLD). To achieve this goal, the project relies on a well-established chemical package of in-house developed, potent, selective, and orally active GPR39 agonist leads, suitable for various types of both ex vivo and in vivo proof-of-concept studies. The project’s main aim is to use these agonist leads to characterize the mechanism of action and physiological role of GPR39 activation, and to build a strong in vivo efficacy package with a focus on the effects of GPR39 activation on obesity, type-2 diabetes, and NAFLD.

Description: The overreaching goal of this project is to integrate genetics and metabolomics data with dietary and lifestyle factors, with the aim of better understanding cardiovascular disease (CVD) etiology, identifying novel biomarkers of CVD, and promoting the development of effective therapeutic strategies to promote cardiovascular health. Specifically, to identify serum metabolite profiles and networks associated with the future risk of coronary heart disease (CHD) in the Danish population. In addition, to examine whether genetic, lifestyle, and dietary factors play a role in the associations between metabolite profiles and the risk of CHD. This proposal outlines an efficient and powerful design leveraging the Danish Inter99 cohort, a well-characterized cohort with existing lifestyle and dietary data with a longitudinal design, and well-documented outcomes, including cardiometabolic risk factors and hard CVD endpoints. Publicly available data from genetic consortiums and other international datasets will also be used.

The postdoc project will not be limited to this project only and options to work on ancillary projects in the field are also possible.

Description: A shared genetic and environmental basis, known as the “common soil” hypothesis, has been postulated to explain the co-occurrence of type-2 diabetes (T2D) and cardiovascular disease (CVD). So far, genome-wide association studies (GWAS) have only identified a handful of shared genomic regions. The limited translation of GWAS signals into effector genes operating in specific cell types, combined with the pathophysiological heterogeneity that characterizes both diseases and the role of the gut microbiome modulating the genetic and environmental basis of cardiometabolic diseases, have hindered the discovery of shared biological mechanisms.

This project aims to identify shared genes and molecular signatures underlying dysglycemia and atherosclerosis by revisiting the common soil hypothesis from a single-cell perspective. We will integrate circulating immune single-cell RNA-sequencing with GWAS summary statistics for glycemic and atherosclerotic traits to identify genes, molecular processes, and cellular programs within and across cell types associated with T2D and CVD. Next, we will use individual-level genetic, imaging, and gut microbiome data to investigate the associations between shared signals and subclinical atherosclerosis and how these associations differ according to preestablished diabetes subtypes or gut microbiota composition.

Collectively, this project has the potential to identify shared genes and molecular signatures underlying hyperglycemia and atherosclerosis, which may spur novel targeted therapies and improve the lives of people living with diabetes.

Description: It is well known that metabolites are continuously being exchanged between organs in mammalian systems via circulation. However, a complete systems-level overview is lacking due to difficulties quantifying metabolic exchange on a higher level. Therefore, to obtain detailed knowledge about metabolism, and circulating-, and organ-specific metabolic flux, analysis should be performed using stable isotope labelled tracers. The aim of the project is to develop workflows for in vivo stable isotope labeling, in vivo flux analysis combined with tissue-specific metabolic flux analysis and interconnected metabolic modeling. The combination will result in unique possibilities to map how metabolites are metabolized and transported in and out from different tissues. The project will focus on metabolic modelling in mice.

Mainly 13C-U-glucose will be used as the tracer in the experiments. However, depending on the research question, other stable isotope labelled tracers can be used too. The methodology will be applied on different projects, such as understanding how brown adipose tissue (BAT) as well as white adipose tissue (WAT) and other tissues metabolically regulate metabolism during cold treatment. In addition, we will map the uptake and secretion of metabolites from different tissues, and track and trace how the metabolites move through the system, and thereby predict systemic changes caused by altered physiological or genetical conditions.