Department of Cellular and Molecular Medicine
Research Interests
The department combines expertises in techniques of Biochemistry, Electrophysiology, Molecular Biology, Cell imaging, Proteomics, Bio-informatics and Animal-model development to acquire novel insights into cellular signaling and communication processes. An additional aim is to decipher the molecular basis for human signal-transduction related diseases and to identify novel therapeutic targets.
About the Department
The department consists of 12 research groups, maintaining close contacts with other departments of the KU Leuven and with the University Hospital.
Major Areas of Research
- Signaling by ions, lipids and protein phosphorylation
- Chromatine structure and function
- Protein structure, (mis)folding and transport
- Cell metabolism, death, autophagy and differentiation
Department Laboratories
Gene Expression Unit
Laboratory of Biosignaling & Therapeutics
Laboratory of Cell Death Research & Therapy
Laboratory of Cellular Transport Systems
Laboratory of Protein Phosphorylation and Phosphoproteomics
Laboratory of Intensive Care Medicine
Laboratory of Ion Channel Research
Laboratory of Lipid Biochemistry and Protein Interactions
Laboratory of Molecular and Cellular Signaling
Laboratory of Molecular Endocrinology
Laboratory of Structural Neurobiology
Switch Laboratory
Gene Expression Unit
Frans Schuit
We are interested in RNA expression of mammalian insulin producing pancreatic beta cells in order to explain how these cells function in normal health and how dysfunction can cause inappropriate release of insulin and diabetes. We study the profound phenotypic changes that occur in rodent beta cells during pregnancy. One of these changes concern serotonin production and secretion by a subpopulation of a heterogeneous beta cell population. We want to understand why only part of the beta cells produces serotonin and what could be the physiological function of this phenomenon. Second, we are interested in genes that are preferentially or specifically expressed in beta cells (the zinc transporter ZnT8 being an example). Third, we discovered by serendipity that genes exist that are expressed in all tissues, except in one tissue. We found for instance that some genes are specifically repressed in beta cells, this in order to prevent the release of insulin under circumstances that this is not appropriate. We were the first to report the existence of these so called “disallowed genes” and we want to better understand how these genes are regulated in normal beta cells and if environmental changes can cause a change in repression.
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Laboratory of Biosignaling & Therapeutics
Mathieu Bollen
The mission of the Laboratory of Biosignaling & Therapeutics is to investigate the structure, function and regulation of protein phosphatase 1 (PP1), and to explore its potential as a therapeutic target. This involves the identification of novel PP1-interacting proteins (PIPs), the mapping of PP1-docking motifs and the analysis of their regulatory effects on PP1. Selected PIPs are also characterized functionally, using various animal and cell models. Current projects mainly address the role of PP1 in chromatin signaling in health and disease, with particular emphasis on mitosis, stem-cell differentiation, wound healing and oncogenesis. Another major focus of the laboratory concerns the development and validation of cell-permeable peptides or small molecules that competitively disrupt subsets of PP1 holoenzymes. These molecules are being used for functional studies (chemical genetics) and as tools for the design of novel cancer combination therapies with kinase inhibitors.
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Laboratory of Cell Death Research & Therapy
Patrizia Agostinis
Defective regulation of cell death, especially in the form of apoptosis, contributes to the development of crucial pathologies including cancer and plays a major role in chemoresistance. Mechanisms regulating cancer cell death also affect the emission of ‘danger signals’ from the stressed/dying cells, which critically define their ‘immunogenic character’ and impact the initiation of immune responses. Our major goal is to understand the molecular mechanisms that control cancer cell death and how different cell death subroutines (e.g. oxidative stress induced apoptosis, ER stress, autophagy-associated cell death) impact immunity and therapeutic outcome. We mainly focus on endoplasmic reticulum (ER) stress and autophagy, two key cellular stress pathways with emerging roles in the modulation of cancer metabolism, inflammation and anti-tumor immunity. To generate fundamental knowledge we use several molecular/biochemical approaches that we finally validate by using suitable cancer models. Our final goal is to contribute to combating cancer by translating the acquired fundamental knowledge into the development of new therapeutic strategies.
CDRT’s specific research topics include:
- ER-mitochondria cross-talk during ER stress and apoptosis
- Role of autophagy in carcinogenesis and therapy response
- Cross-talk between cancer cell death and innate immunity
Development of anticancer treatments harnessing immunogenic cancer cell death
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Laboratory of Cellular Transport Systems
Peter Vangheluwe
Research of the LabCTS team is focused on the molecular structure and function, the cell biological and (patho)physiological role of several members of the P-type ATPase family of transporters. These molecular machines generate vital ion or lipid transmembrane gradients across various biological membranes, driving many basic physiological processes. More specifically, our research concentrates on two classes of P-type ATPases.
One class concerns the intracellular Ca2+ transporters SERCA and SPCA (P2-type ATPases), which contribute to crucial processes such as contraction, secretion, but also to vital decisions like cell growth, differentiation, multiplication and death. Deranged P-type mediated active Ca2+ transport is associated with the genodermatoses known as diseases of Darier and Hailey-Hailey, but also with heart failure and cancer.
Expertise in the field of Ca2+ transport ATPases is further valorized in the study of a novel, ubiquitous class of P-type ATPases, named P5-type. With an unknown substrate specificity they represent one of the last blind spots on the P-type ATPase map. Here we focus in particular on ATP13A2, a lysosomal member associated with a Parkinsonism type of neuropathology known as Kufor-Rakeb syndrome.
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Laboratory of Protein Phosphorylation and Phosphoproteomics
Johan Van Lint
We investigate the regulation of (patho)physiological processes via reversible protein phosphorylation, and explore the therapeutic potential of the kinases and phosphatases involved. Focus is on Protein Kinase D (PKD) and Protein Phosphatase 2A (PP2A), but increasingly also on broader (kinome and phosphatome wide) approaches to systematically identify kinases/phosphatases that are implicated in (patho)physiological processes.
We study the role of PKD2 in tumor angiogenesis/invasion and we develop PKD inhibitors. We also identify protein kinases that could serve as targets for the treatment of sarcomas (with UZ Leuven) or of KRAS or EGFR mutant NSCLC (EU Lungtarget project).
For PP2A, the focus is mainly on its tumor suppressive abilities and its deregulation in cancer, but we also study its role in neurodegenerative and cardiovascular diseases, and in basic cell biological process (mitosis, cell migration).
We apply (and further develop) mass spectrometric approaches for (phospho)proteomic and lipidomic analysis to solve biomedical questions.
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Laboratory of Intensive Care Medicine
Greet Van den Berghe
Our overall research objective is to expand the current knowledge and unravel key pathways underlying critical illness-induced organ failure, thereby identifying potential therapeutic targets to enhance recovery. We focus on endocrine and metabolic underlying mechanisms (e.g. glucose and nutrient toxicity, neuroendocrine dysfunctions, impaired autophagy and mitochondrial dynamics, epigenetic alterations, genetic predisposition) of organ-specific problems evoked by critical illness (muscle atrophy and loss of integrity, bone loss, altered function of the adipocyte, cholestasis and liver dysfunction, kidney failure, brain dysfunction).
Our group combines a research laboratory with a large clinical Intensive Care Unit (> 2000 patients per year). This unique setting allows a fast and effective interaction among clinicians and basic researchers within the team. Our translational research program comprises carefully designed studies in critically ill patients, studies in our unique animal models of critical illness, several cell culture models as well as molecular and cellular studies of precious patient samples.
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Laboratory of Ion Channel Research
Thomas Voets
The mission of the Laboratory of Ion Channel Research is to study ion channels in all their aspects. This includes the analysis of their molecular and biophysical properties, their transport and function in various cell types, their (patho)physiological role in different organs and in vivo using various animal models, and their role in inherited and acquired human diseases. The Laboratory of Ion Channel Research also focuses on the development of selective pharmacological tools that may translate fundamental findings to novel clinical therapies, in collaboration with academic, clinical and industrial partners. Currently, the main focus is on the superfamily of Transient Receptor Potential (TRP) channels. However, the technology and expertise available in the Laboratory of Ion Channel Research can be readily applied to various types of ion channels and (patho)physiological problems.
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Laboratory of Lipid Biochemistry and Protein Interactions
Paul P Van Veldhoven
To conduct high quality fundamental research, focusing on the role of peroxisomes in complex cellular processes (lipid metabolism, ROS/RNS metabolism, organelle dynamics and dysfunctions) in mammals and to provide insight in inherited and other human disorders linked to these organelles via cellular studies and mouse models.
To expand/build a platform for specialized lipid analysis.
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Laboratory of Molecular and Cellular Signaling
Humbert De Smedt
LMCS focuses on the mechanisms of cellular Ca2+ signaling in normal and in pathological conditions. LMCS is a leading group in Ca2+ signaling with an excellent international reputation. We study the role of Ca2+ in fundamental cellular processes, including cell death, autophagy, cell differentiation and intercellular communication via connexins. Our molecular approach focuses on key signaling proteins such as the inositol 1,4,5-trisphosphate receptor (IP3R), which is a ubiquitous player in the generation and regulation of cytoplasmic, organellar and intercellular Ca2+ signals. The interactome of the IP3R includes e.g. protein families involved in mitochondrial metabolism, cell death and autophagy, and proteins linking Ca2+ to other signaling networks. We have unique expertise in the detection of cellular and subcellular Ca2+ by using radioactive Ca2+ fluxes and state-of-the-art fluorescent imaging techniques in single cells and cell populations from animal models and patients. In collaboration with clinical research groups we investigate disturbed Ca2+ signaling in e.g. cancer cells, patient cells related to neurodegenerative disorders and polycystic kidney disease. We develop strategies to interfere with Ca2+ signaling in these conditions by using specific peptides targeting the IP3R interactome and connexin hemichannels. In collaboration with structural chemistry experts we develop peptido-mimetic reagents for future clinical applications.
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Laboratory of Molecular Endocrinology
Frank Claessens
At the Molecular Endocrinology Laboratory, we study a selection of topics on the cellular and molecular actions of male hormones.
1. We have a special interest in the molecular mechanisms of action of the androgen receptor during the regulation of gene transcription and cell cycle.
2. We study these functions of the AR in prostate cancer: we analyze the roads leading to resistance to current hormonal treatments and develop new experimental AR antagonists.
3. The contribution of androgens to the gender differences in the musculoskeletal system are investigated with the help of animals in which the AR is inactivated in satellite cells, osteoblasts, osteocytes or osteoclasts. This is combined with in depth in vitro analysis of the affected cellular signaling pathways.
4. Sex hormone binding globulin is a major player of androgen and estrogen action in humans. We study its role in aging male and a set of endocrine pathologies.
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Laboratory of Structural Neurobiology
Chris Ulens
The Laboratory of Structural Neurobiology aims at understanding the relationship between structure, function and pharmacology of ion channels. We pursue three-dimensional structures of ion channel homologs using X-ray crystallography. Mechanistic insight into channel function is obtained in combination with structure-guided mutagenesis and electrophysiological recordings. Collectively, this information is used to rationally design new drugs to better treat disorders related to abnormal ion channel function. Our current structure targets include family members of the class of pentameric ligand-gated ion channels (nicotinic acetylcholine receptor, 5-HT3 serotonin receptor, GABAA/C receptor), TRP channels and HCN pacemaker channels.
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Switch Laboratory
Frederic Rousseau
Our research is focused on understanding the mechanisms gearing protein folding and misfolding and their relation to human disease. In particular we are investigating how protein aggregation affects the cellular interactome by suppressing native interactions but also by introducing novel aggregation-specific interactions. The latter are especially relevant as they are usually associated to gain of function activities such as neurotoxicity (neurodegeneration) or cell proliferation (cancer).
First we aim at creating a more accurate picture of the aggregation propensity of the human proteome and the effect of genome variability hereupon. In order to achieve this we created a set of bioinformatics tools that capture the sequence-specific determinants of protein aggregation and performed a genome-wide analysis on the impact of aggregation on disease-associated mutations. In doing so we found that aggregation is not restricted to a set of amyloid diseases but that many metabolic diseases and cancer are also affected by aggregation.
Second, we aim at understanding how gain-of-function of protein aggregates is effected in both cancer and neurodegeneration by mapping the aggregation-specific interactome in these different contexts.
Our experimental approach is interdisciplinary, combining bioinformatics, biophysical analysis, as well as mammalian cell culture and model organisms such as zebrafish and mice.
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Education
The department of CMM has a long tradition in teaching basic sciences (Biochemistry, Molecular Cell Biology, Pharmacology and Physiology) to students of the Biomedical and Exact Sciences groups. These teaching duties have recently been extended to include specific aspects of clinical training in anaesthesia and intensive care medicine.