Work Package 5.

The endo-lysosomal processes in metabolic disease development and therapeutic efficacy.

University Medical Center Groningen, Groningen, The Netherlands

Jan Albert Kuivenhoven

Several lines of evidence highlight the importance of the endo-lysosomal system in the regulation of glucose and lipid metabolism but how they contribute to these pathways remain unclear. In addition, many therapies (such as Antisense oligonucleotides (ASOs) to treat hypercholesterolemia) are dependent on the endo-lysosomal system to enter the cell, how the endo-lysosomal system is involved in therapeutic potency is unclear. In this work package we will investigate how components of endo-lysosomal processes in different tissues contribute to the regulation of glucose and lipid metabolism and therapeutic efficacy.

PhD projects in this Work Package:

PhD student 11 – The contribution of the endosomal sorting machinery to metabolism 

 University Medical Centre Groningen, NL

Bart van de Sluis, a.j.a.van.de.sluis[at]umcg.nl

The PhD student will investigate the metabolic effects of tissue-specific deficiency of the endosomal sorting machinery on circulating lipids, glucose levels and adipokines. The mechanisms by which the endosomal sorting machinery in adipose tissue regulates metabolism, including lipid and glucose metabolism, and atherosclerosis will be studied. The contribution of differential expressed endo-lysosomal proteins in the liver of NAFLD/NASH patients to the pathogenesis of NAFLD/NASH will be investigated, and novel reagents to deliver gRNAs into cells and/or tissue to edit the genome will be developed.

PhD student 12 – Relevance of endosomal trafficking pathways for human lipid metabolism

University Medical Centre Groningen, NL

J.A. Kuivenhoven, j.a.kuivenhoven[at]umcg.nl

The PhD student will be involved in data mining of large-scale human genetic epidemiological studies to assess the impact of common and rare genetic variations in genes of the endo-lysosomal network on cardio-metabolic diseases. The variants will be functional validation using in vitro and in vivo models. In addition, together with partners novel players in the endo-lysosomal system will be identified using innovative pipeline.

PhD student 13 – Role of endothelial lipoprotein transport for adipose tissue integrity and dyslipidemia (position open)

University Medical Centre Hamburg-Eppendorf, DE

Jörg Heeren, heeren[at]uke.de

The PhD student will investigate the intracellular route and the functional role of endothelial lipoprotein trafficking in adipose tissues and metabolism in mice. The contribution of endothelial lipoprotein receptors to the development of diet-induced obesity and dyslipidemia will be investigated in mice lacking e.g. scavenger receptor B1 (SR-BI) in endothelial cells. Transgenic mice will be studied under conditions of fasting, feeding and cold exposure by innovative technologies including indirect calorimetry and tracer based metabolomics.

PhD student 14 – The role of endo-lysosomal membrane proteins for energy metabolism in white and brown adipose tissues 

University Medical Centre Hamburg-Eppendorf, DE

Jörg Heeren, heeren[at]uke.de

Pablo Sáez, p.saez[at]uke.de

The PhD student will investigate the effects of endo-lysosomal membrane proteins such as the cation channel TMEM176A/B on lipid storage, release and combustion in white and brown adipose tissues, under conditions of cold-induced thermogenesis and diet-induced metaflammation. The effects of adipose-specific transgenic mice for glucose and lipid trafficking will be investigated by advanced cell biological tools such as microfluidics and micropatterning technologies in combination with metabolic tracer and energy expenditure studies.

PhD student 15 – Evaluating the endosomal transport and efficacy of therapeutics for metabolic liver diseases progressing to cancer

InteRNA technologies, Utrecht, NL

Roel Schaapveld, schaapveld[at]interna-technologies.com

You are employed and the research is done at InteRNA. In addition, you are registered at the Utrecht University, NL, where you will do the thesis defence.

The PhD student will study the endo-lysosomal trafficking of therapeutics by monitoring the fate of fluorescent labelled therapeutics, such as lipid nanoparticle-coupled miRNAs or guided RNAs for CRISPR-based approaches.
The role of endo-lysosomal network on the fate of therapeutics by inhibiting key regulators of endo-lysosomal transport will be explored and will determine the impact of altering endo-lysosomal transport on the treatment efficacy of novel RNA-based therapeutics in mouse models of diseases, such as liver cancer.

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