We study the molecular mechanisms of intracellular protein trafficking and cell polarity and how these mechanisms contribute to health or, when disrupted, to (age-related) human disease.
Our focus is on human diseases in which disrupted intracellular protein trafficking or cell polarity plays a prominent role. This includes elucidating their pathogenesis, the development of patient-specific stem cell-based organoid models and lead identification for novel therapeutic.
Our favourite model to study intracellular protein trafficking and cell polarity is the intestine. A healthy intestine is crucial for the resilience and healthy aging of organisms. The intestinal wall is a dynamic barrier that is responsible for the exchange of nutrients, regulation of metabolism, defence against pathogens and maintenance of immune tolerance to commensal bacteria in the gut lumen. Impairment of intestinal homeostasis, nutrient digestion/absorption capacity and the gut wall barrier (known as leaky gut syndrome), occurs during aging and is associated with the development of age-related neurodegenerative diseases such as Parkinson disease. The role of the intestine in aging is further exemplified by the effect of dietary calory restriction on life span, as the intestinal wall is the first site where caloric or nutritional adjustments impact the organism.
The gut wall is made up by a single layer of intestinal epithelial cells, supported by fibroblasts, muscle cells and nerve cells that connect the intestinal wall to the brain. Intestinal epithelial cells are extremely compartmentalized, illustrated by the segregation of their cell surfaces in three structurally distinct domains: the brush border domain that faces the gut lumen, the lateral domain that faces neighbouring cells and the basal domain that faces the underlying fibroblasts, immune, muscle and nerve cells. Each domain is equipped with unique protein compositions that provide functional specificity. Although such polarized organization is essential for intestinal homeostasis, nutrient digestion/absorption and gut wall barrier and, hence, organismal health, the responsible molecular mechanisms are not well understood.
Defective intracellular protein trafficking and cell polarity are at the basis of many human (age-related) diseases, including cancers and neurodegenerative diseases. We aim to intervene in derailed pathways that control or are controlled by intracellular protein trafficking and cell polarity to combat such diseases. Understanding the exact role of intracellular trafficking and cell polarity in the various pathological conditions is crucial, which in our laboratory has led to the identification of leads and pre-clinical screening of repurposable drugs for therapeutic intervention in specific human diseases.
The brush border surface of intestinal epithelial cells is a highly polarized subcellular structure with a unique protein composition. The brush border is crucial for the absorption of dietary nutrients as well as oral medication, and acts as a tumour-supressing subcellular unit. The brush border shows an aging-associated functional decline which is not understood. We aim to understand the molecular mechanisms that control brush border function. Our approach is to identify and study inherited diseases that are clinically characterized by severe congenital diarrhoea and generalized malabsorption of dietary nutrients, indicative of brush border defects. We identified novel genes that cooperate in molecular pathways that secure the unique protein composition and integrity of the brush border and prevent aging-related cellular damage. Furthermore, mutations in these genes also affect protein trafficking and cell polarity in other organs (e.g., the liver and, during prenatal life, the placenta), which is an often-overlooked co-determinant in disease development and organismal health. Current work focusses on 1) unravelling the function of these genes in intracellular protein trafficking and cell polarity in relevant organ systems, 2) revealing the pathogenic mechanisms of mutations in these genes and 3) identifying leads for therapeutic intervention.
Mutations in genes that are involved in intracellular protein and lipid trafficking are well-established risk factors for Parkinson disease (PD), the second-most common age-related neurodegenerative disease. PD is associated with intestinal symptoms which often precede the onset of motor and neuronal symptoms by many years. An increasing body of evidence indicates that intestinal dysfunction (e.g., altered microbiome, increased leakiness of the gut wall, low-grade inflammation) may play a pivotal role in the development of PD. While many studies focus on the role of PD-associated genes in the brain, most of the PD-associated genes are also heavily expressed in the intestinal tract. We study the function of these genes in the intestinal tract and investigate how PD-associated mutations in these genes affect (the interplay between) intestinal epithelial cells (e.g., gut wall permeability) and enteric nerve cells, and how this can be modified by the gut microbiome. For this we make use of PD iPSC-derived nerve cell-innervated gut organoids in co-culture with PD-relevant gut microbes.
The use of (patient-derived) stem cell-based organoids has been instrumental to study fundamental processes in cell and developmental biology and the pathogenesis of diseases. Cellular processes and disease phenotypes often change with age. However, genotype/phenotype-by-age associations in organoid models have been largely ignored. We investigate age range-related genotype/phenotype associations in human organoid models.
University Medical Center Groningen (UMCG)
Department of Biomedical Sciences of Cells and Systems
Sven van IJzendoorn - Intracellular trafficking & cell polarity
Internal Zip code FB32
Antonius Deusinglaan 1
9700 AD Groningen
The Netherlands
Visiting Address
University Medical Center Groningen (UMCG)
Department of Biomedical Sciences of Cells and Systems
Antonius Deusinglaan 1
Building 3215, 7th floor, room 747
9713 AV Groningen
The Netherlands
