The discipline of Biomedical Sciences addresses global challenges such as obesity, cancer, and cardiovascular, autoimmune and infectious diseases. Our programme capitalises on a rich diversity of thematic in genetics, development, microbiology immunology and physiology to offer a stimulating environment to train young scientists toward autonomous and responsible scientific work. The acquisition of fundamental knowledge and a wide range of advanced and transferable skills is achieved through a versatile training program that expands scientific culture and critical thinking. Research projects are embedded in an arena of cutting edge cores facilities that provide personalized training and the proximity of the hospital offers a unique interface between basic and clinical research.
Obesity is a key factor predisposing to hepatic metabolic disorders commonly referred as non-alcoholic fatty liver disease (NAFLD). Hepatocellular carcinoma (HCC) can develop in the setting of NAFLD and considering the obesity pandemic, incidence of both NAFLD and HCC is expected to dramatically increase in the future. The lab investigates the molecular mechanisms involved in NAFLD and its progression towards HCC. We are particularly interested in the role of the PI3K/PTEN pathway and of epigenetic mechanisms involving microRNAs and RNA-binding proteins in these pathologies. In addition to common lab techniques, state-of-the-art methodologies are applied to investigate NAFLD and liver cancer development using in vivo animal and in vitro cell models, human samples and omics analyses.
We are studying genetic disorders of hemostasis and thrombosis, e.g. fibrinogen deficiencies. These affect either the quantity or the quality of circulating fibrinogen, the precursor of the major protein of the blood clot, fibrin. Fibrinogen is a hexamer made of two copies of three chains, encoded by a three-gene cluster on human chromosome 4. We investigate the molecular mechanisms by which fibrinogen gene mutations lead to disease and other mechanisms influencing fibrinogen levels and function. The zebrafish animal model is used for these projects. The discovery of novel mechanisms determining fibrinogen levels in the circulation is clinically relevant since a high fibrinogen level is an independent risk factor for cardiovascular disease.
The CANSEARCH research laboratory has more than 10 years’ experience in pharmacogenomics research and is collaborating internationally in this field. The laboratory’s expertise includes the application of pharmacogenomics research to tailor drug dosing in pediatric cancer treatment and to apply genetic models to predict outcomes in various pediatric cancers and in the hematopoietic stem cell transplantation (HSCT) setting. The laboratory currently has different pharmacogenomics studies as principal investigator, including one open in 20 countries (Polymorphism and Busulfan Pharmacokinetic study in Acute lymphoblastic leukaemia (ALL SCT ped Forum study; clinicaltrial.gov ID: NCT01949129; NCT02670564) , as well as in the pharmacogenomics study in myeloid leukaemia.
The innate response is the cornerstone of the immune response against viral infections. Part of the innate response starts with the detection of viral infection by cytoplasmic sensors of the RIG-I-like receptors family that discriminate between dsRNA structures of viral and cellular origin. Viruses have developed a phenomenal capacity for adaptation, making this discrimination and detection difficult. Cells, on their side, have evolved to produce RNAs endogenously that have lost self-attributes, and thus will activate RLRs. Moreover, beyond their function of specifically binding viral RNAs, these cytoplasmic sentinels have also developed the ability to directly restrict viral replication. The intimate knowledge of these mechanisms is essential to develop new therapeutic approaches.
Our research group mainly investigates the mechanisms of cardiogenesis and cardiac cells. Specifically, we study cells featuring trisomy 2,1 with the aim of uncovering the differentiation of human pluripotent stem cells - either embryonic or induced pluripotent stem mechanisms at the basis of congenital heart defects in patients with Down syndrome. We also study the potential of cardiac and skeletal differentiation of mesoangioblasts, a subpopulation of perivascular stem cells with great potential for muscle regeneration, in particular of genetic diseases such as muscular dystrophy. Our long-term goal is translational, i.e. the set-up of muscle regeneration strategies, based on tissue engineering, that are easily transferrable to the clinical setting.
Stimulation of glucose transport is one of the first line of defense for the myocardium undergoing ischemic stress. Animal models and clinical studies show that the diabetic myocardium undergoes increased myocardial injury and poorer recovery of function, linked to a reduced capacity to stimulate glucose metabolism during ischemic stress. We investigate cellular mechanisms that in response to the diabetic dyslipidemia may dysregulate metabolic stress-stimulated glucose transport. Complementary in vitro and in vivo experimental approaches are used. Isolated adult rat cardiac myocytes are chronically exposed in vitro to lipids as a model of the diabetic dyslipidemia. In vivo experiments in an animal model of type II diabetes attempt to complement and confirm positive in vitro findings.
Phagocytosis is the process by which eukaryotic cells ingest big particles like bacteria. To understand this process, we are making use of a model phagocytic cell, the amoeba Dictyostelium discoideum. Amoebae phagocytose bacteria to feed upon them, and the molecular mechanisms involved are very similar to those observed in mammalian phagocytic cells. Using this simple system, we are studying the role of various gene products in phagocytic cells. Our main aim is to understand how a cell can kill different types of bacteria. Our results indicate that different and largely uncharacterized mechanisms ensure killing of different types of bacteria. Understanding how non-pathogenic bacteria are killed is essential to then study how pathogenic bacteria escape intracellular killing.
We want to determine the origin of insulin-producing β-cells during embryonic development and in adults, whether during normal homeostasis or pancreatic regeneration after total β-cell ablation, using many transgenic mouse models and human pancreatic islets. Regeneration of new β-cells in the diabetic pancreas is the main research topic of the lab. We try to help devising innovative cell-based replacement therapies to treat diabetes. We have generated transgenic mice in which specific pancreatic cell types can be conditionally ablated. We have reported that β-cell loss in adult mice is followed by spontaneous β-cell regeneration, which mostly relies on the reprogramming of fully differentiated glucagon-producing α-cells into insulin producers.
Physiologically Based Pharmacokinetics modeling (PBPK) use in clinical setting has become an important challenge to help clinicians tailoring medication based on genetic, environmental as well as patients’ characteristics. Drug-drug interactions (DDIs) are of particular clinical interest because of their high prevalence among polymorbid patients and their potential deleterious clinical implications. DDI prediction represents one of the most promising domains for a successful use of PBPK. Drug metabolic enzymes and transporters are the most important factors in interindividual variability. Several in-vitro models are used to generate data evaluating metabolism and transport of drugs. These data as well as in-vivo data are incorporated in the software for an optimal medication adjustment.
The Genomic Research Laboratory is actively involved in the development of methods in metagenomics and their application for medical research and diagnosis. Research interests: • Investigation of the mechanisms underlying Staphylococcus aureus biofilm formation, intracellular survival and antibiotic resistance • Development of rapid antimicrobial susceptibility testing (AST) methods
The interleukin (IL)-1 family includes seven pro-inflammatory cytokines and four members with established or hypothetical antagonist activity, including IL-38. Agonistic IL-1 family cytokines have specific roles in innate and adaptive immunity, while antagonists limit uncontrolled inflammation and immune responses. Little information is available to date concerning expression and function of IL-38. Our working hypothesis is that IL-38 acts as a naturally occurring inhibitor of inflammation and might possess therapeutic properties in specific immune-mediated inflammatory diseases. The aim of this project is to further study the biology and potential anti-inflammatory properties of IL-38 using cultured human and mouse cells and different mouse models of disease.
The Geneva Platelet Group co-directed by Jean-Luc Reny and Pierre Fontana is an interdisciplinary group working with complementary approaches in a truly translational way on the issues of platelet function and antiplatelet drugs. Investigational approaches include basic science, pharmacological, clinical and epidemiological research.
My laboratory is interested in the role of cytokines of the interleukin (IL)-1 family in the immune and inflammatory responses. IL-1 is a cytokine that is critical in the innate immune response to different types of endogenous or exogenous noxious agents. In addition, other IL-1 cytokines such as IL-18, IL-33 and IL-36 share structural characteristics, bind to the same family of receptors, and stimulate similar intracellular signals as IL-1. Interestingly, natural inhibitors, including receptor antagonists and decoy receptors exist for all the IL-1 cytokines. Our research group is generating and working with different genetically modified mouse lines, to elucidate the role of these cytokines in several models of inflammatory diseases.
Le groupe de recherche s'articule autour de deux axes en neurobiologie a) recherche fondamentale et b) recherche translationnelle intégrant les compétences de chercheurs en biologie, biochimie et chimie, de bio-informaticiens et de cliniciens. L'axe de recherche fondamentale cible la découverte de nouveaux mécanismes dans la neurotoxicité de certains xénobiotiques sur des modèles in vitro de la barrière hématho-encéphalique. L'axe de recherche translationnelle a comme objectif l'identification, le développement et l'implémentation de marqueurs diagnostiques et prognostiques de pathologies cérébrales tels que les accidents vasculaires cérébraux et les traumatismes crâniens.
The projects of the Collart laboratory deal with the Ccr4-Not complex, conserved across the eukaryotic kingdom and a central regulator of gene expression that acts from mRNA synthesis to degradation of proteins. The Collart laboratory studies this complex regulator in the yeast S.cerevisiae where powerful genetic tools can be combined with biochemical studies. Their working model is that the Ccr4-Not complex works as a "chaperone platform", regulating dynamic functional interactions between cellular partners. By interacting with translating ribosomes and chaperones, it has the ability to interact with newly synthesized proteins and "deliver" these proteins to their cellular partners in a functional way. The projects of the Collart laboratory are targeted towards addressing this model.
Intracranial Aneurysms are deformations of cerebral vessels that form, progress and may rupture exposing patients to severe disabilities or death. Multiple factors interact at each stage of the disease to result in lesions' initiation and progression. Our research group federates, harmonizes and standardizes information collection from different sources globally. Genetic, biological, imaging and clinical data are analyzed to progressively refine a biomechanical disease model and a statistical phenomenological mode. Both models are used to simulate cerebro-vascular remodeling and offer decision support. In particular, the lab focuses on establishing shape characteristics as a biomarker of disease stage and identifying biomarkers of aneurysm wall stability.
Connexins (Cxs) and pannexins (Panxs) form transmembrane channels that control intercellular communication and contribute to vascular homeostasis. Mutations or polymorphisms leading to channel dysfunction have been implicated in several human vascular pathologies, including atherosclerosis, thrombosis and lymphedema. Our research group is interested in the mechanisms by which Cxs and Panxs participate in cardiovascular physiology and disease. In particular, the lab focuses on the transcriptional regulation of Cxs and Panxs in response to wall shear stress, the frictional drag force of the flowing blood on the vascular wall. Moreover, we are studying the Cx and Panx interactome, identifying novel protein partners and their role in vascular (patho)physiology.
We are interested in body fluid homeostasis with a focus on renal handling of water and electrolytes. We are studying the adaptation of renal tubular cell transport properties and metabolism to various amounts of dietary sodium and potassium ions; the coupling between transcellular and paracellular sodium transport and the effect of variations of sodium transport by renal tubular cells on primary cilium length and function. In addition, using several models of chronic kidney disease such as unilateral ureteral obstruction and inducible glomerular or tubular injury, we are currently assessing the role of the mineralocorticoid receptor and dietary sodium and potassium intakes in the progression of renal injury.
Inflammation and fibrosis. The extracellular matrix (ECM) is continuously renewed according to finely tuned processes in which fibroblasts are main actors. Fibrosis results from dysregulated synthesis and degradation of ECM. Inflammatory events potently modulate fibrotic processes. We have taken systemic sclerosis (SSc) as a disease model, characterized by fibrosis of the skin and internal organs, vasculopathy and auto-immunity. We have developed several in vitro models to study the dynamic relationships between fibroblasts and cells of adaptive and innate immunity, generated form skin biopsies from SSc and healthy individuals. The results show that the quality and intensity of fibroblasts responses are greatly influenced by the cell types and products to which they are exposed.
Cell adhesion between cells or to the extracellular matrix is essential to maintain the healthy state of a tissue. During development, but also in pathologies such as cancer or fibrosis, alterations in the dynamic remodeling of the cell-cell and cell-extracellular matrix contact leads to the formation of new tissues and organs, but will also lead to life-threatening pathologies. By using a structure-function approach we study the structural assembly of integrin-containing cell-matrix adhesion sites, and we would like to understand how they are regulated by mechanical tension, by receptor tyrosine kinases signaling and by the metabolic status of cells. Fluorescent proteins and live-cell imaging are used to track integrin receptors and their adapters to identify new therapeutic targets.
The translational direction of our research aims at drug discovery targeting the Wnt signaling pathway in cancer, principally breast cancer. Our pipeline encompasses high-throughput screening, hit-to-lead optimization, and animal PK and PD studies, culminating with early phase clinical trials.
CCR5, a chemokine receptor and a member of the GPCR superfamily, is the principal HIV entry coreceptor and a promising target for anti-HIV medicines. For over a decade we have been using a range of protein engineering approaches to discover and optimize analogs of the natural chemokine ligands of CCR5, culminating in the successful translation of our most promising chemokine analog into clinical trials. In parallel, our basic science research makes use of the chemokine analogs that we identified, together with innovative cell-based assays, as tools to study the biology and pharmacology of CCR5. Despite their structural similarity, these molecules show striking differences in anti-HIV potency, induction of receptor endocytosis and intracellular trafficking, and receptor signaling activity.
We study how mitochondria integrate and generate metabolic signals controlling the coupling of glucose recognition to insulin exocytosis. Current work investigates generation, intracellular transport, and mechanism of action of glutamate in beta-cells and brain; related to energy homeostasis. We are particularly interested in the Glud1 gene that encodes for glutamate dehydrogenase. Beside tissue-specific knockouts, we study Glud1 activating mutations giving rise to hyperinsulinemia (beta-cell), hyperammonemia (liver), and epilepsy (brain).
Molecular and cellular immunology, with a current focus on the regulation of anti-tumor T cell responses in mouse model systems.
Rhinoviruses (RV) and enteroviruses (EV) are leading causes of infections in humans. Although closely related at a genetic level, they are characterized by an important genetic variability, illustrated by the existence of more than 250 different types. This genetic heterogeneity is paralleled by an important phenotypic diversity. RV infection is restricted to the respiratory tract, whereas EVs can cause viremia, spread to multiple sites, and have been associated with over 20 distinct syndromes, from common cold to encephalitis. Our research explores the pathogenic diversity of RV and EV. Using molecular, cellular and biochemical tools, we aim to determine and characterize the genetic factors that underlie clinically relevant phenotypic traits, such as virulence and neurotropism.
The human infection with the hepatitis C virus (HCV) is associated with insulin resistance (IR) and increased risk of type 2 diabetes. We plan to analyse the mechanisms of HCV-associated IR using in vitro models (human and mouse cell lines transduced by lentiviral vectors expressing the HCV core protein), mice infected with AAV8 expressing the HCV core protein and carefully selected chronic hepatitis C patients subjected to euglycemic hyperinsulinemic clamp analyses before and after antiviral therapy. Preliminary results show that HCV induces IR mostly by modifying the insulin sensitivity of uninfected, extrahepatic tissues (muscle, adipose tissue), suggesting that HCV-induced IR proceeds via endocrine mechanisms involving specific hepatokines.
DNA methylation can block transcription factor (TF) recruitment to their binding sites. Surprisingly, we have identified a few TFs called “Super Pioneer Transcription Factors” (SPFs) that are able to bind methylated DNA in compact chromatin and induce nucleosome remodeling, DNA demethylation and transcription activation: these results add more complexity to the relationship between TF binding and epigenetic modifications. We are currently focusing on 3 projects: 1) define the rules that govern the relationship between TF binding and DNA methylation, 2) identify all SPFs and investigate the mechanisms underlying SPF-dependent DNA demethylation, and 3) provide a proof of concept for the use of SPFs in therapeutic approaches for two pathological conditions: cancer and obesity.
The main topic of our research focuses on the study of molecular mechanisms involved in sex determination, differentiation of gonads and testicular function. In particular, we are developing two axes of research: 1) Identification of novel factors involved in disorders of sexual development, and 2) Role of growth factors of the IGF family in mediating testis development and function
Circadian oscillation of biological processes has been described in most of the light-sensitive organisms on earth. It reflects the existence of underlying intrinsic biological clocks with near 24 h oscillation periods. There is an evidence for connection between metabolic pathologies and the circadian clockwork. The long-term goal of our laboratory is to identify the molecular basis of circadian rhythmicity in rodent and human peripheral tissues in physiological, and in obesity and type 2 diabetes conditions. We have setup the methodology for long-term recording of circadian reporter oscillations in human primary cells from metabolic tissues at population and single cell levels. In addition, we are interested in the connection between clock and cancer, in particular the thyroid cancer.
The main interests of our lab are the molecular mechanisms underlining metabolic diseases, primarily obesity and insulin resistance. The projects involve using state-of-art technologies and in vivo animal models, in vitro systems, cohorts of human patients, and lineage tracing studies, generally aiming at developing strategies for treatment of dyslipidemia, diabetes and obesity. Research interests include the roles of the adipose tissue and the gut in the regulation of metabolism; and the importance of the gut microbiota and the immune system in orchestrating the energy homeostasis. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota and the host response to combat disease and improve health.
We have a longstanding experience in the implication of smooth muscle cell (SMC) heterogeneity in atherosclerosis. Using porcine coronary artery smooth muscle cells as in vitro model, we identified S100A4 as a marker of atherosclerotic SMCs, in both pig and human. Our recent results suggest that the extracellular form of S100A4 plays an unexpected role in SMC phenotypic transition associated with pro-inflammatory features. We are deciphering in vitro the signaling pathways involved in intra and extracellular S100A4-induced SMC phenotypic transition. In vivo, we study the role of S100A4 in the progression of atherosclerotic plaques in ApoE knockout mice. We are developing an atherosclerosis model with SMC tracing and SMC-specific deletion of S100A4 using the CRISPR-Cas9 approach.
Our lab studies the subcellular organization of opioid receptor signaling in response to chemically distinct opioid ligands. Previously we have shown that opioid drugs differ from endogenous peptides in the cellular location at which they drive receptor activation. It suggests that some drug-specific effects and abuse responses may be explained by what pools of receptors a certain drug is interacting with. Now we aim to unravel how location-specific signaling contributes to opioid drug action and pathology. In this newly established SNSF Eccellenza-funded group, we will combine novel nanobody-based biosensors, live-cell microscopy, neurobiology, pharmacology, and transcriptomic approaches to answer how clinically important signaling systems function on the cellular level.
Viruses are highly adapted to their host organism in order to replicate successfully. On a molecular level my team works on understanding the interplay of virus and host factors within the host cell and develops tools to identify new host proteins, which are either required for or which counteract virus replication. On organism level we are addressing how acute viral infections, e.g. with influenza A virus, disturb the fine-tuned balance of microbial communities in our body, and how these disturbances affect short and long-term physiological functions of the host.
The Soldati group aims at understanding the cellular and molecular mechanisms of phagocytosis and their relevance to host-pathogen interactions. We use the social amoeba Dictyostelium as a model organism as it is a professional phagocyte very similar to mammalian phagocytes of the innate immune system in morphology and behaviour, but which is genetically and biochemically tractable. We study conserved mechanisms of cell-autonomous defences against mycobacterial infections, using this powerful alternative host model. During infection with pathogenic Mycobacterium marinum, we study aspects of nutritional immunity, acquisition of metabolites, as well as the interference with membrane integrity and trafficking. We have used this model to identify novel anti-infective compounds.
Protein translation initiation is a key step in the regulation of cell growth. Consequently, dysfunctions of the translational machinery are associated with many human tumours. Our group studies global and gene-specific regulation of initiation in mammalian cells. The objective is to characterise the elements both cis and trans which control the recruitment of mRNAs onto polysomes under defined physiological conditions. More specifically, we are analysing the function of the eukaryotic initiation factor eIF4E3, which binds the 5’ mRNA cap but is not under the control of the 4EBPs. Additionally, using high-throughput polysomal/ribosomal profiling we are exploring the impact of promoter heterogeneity on the protein readout.
Our laboratory has been mainly interested in the role of CD44 and its interaction with hyaluronate (HA) in skin aging. CD44 is a polymorphic transmembrane glycoprotein and the principal cell surface receptor of HA. We have observed a decrease of epidermal CD44 and HA in dermatoporosis, a term that we proposed for a chronic cutaneous insufficiency/fragility syndrome of the elderly. We have shown that dermatoporosis is due to the dysfunction of hyalurosome which is a putative multimeric macromolecule complex composed of molecules involved in HA metabolism and cell signaling in keratinocytes, such as CD44, HB-EGF and erbB1. According to our studies, epidermal Lrig1+ stem cells, Wnt/-catenin pathway, calcium signaling and p16Ink4a may also play a role in the pathogenesis of dermatoporosis.
The goal of our research is to understand the molecular mechanisms through which specific junctional proteins are involved in human disease, focusing on hypertension, glaucoma and cancer. Apical junctions comprise tight junctions and adherens junctions, and their components are expressed in epithelial and endothelial cells. Apical junctions are involved not only in canonical adhesion and barrier functions, but also in mediating the cellular and tissue response to mechanical, hormonal, pathogenic and other inputs. We are focusing our studies on proteins which are involved in the above-mentioned diseases, and we use cellular and animal models, also with the perspective of developing new diagnostic and therapeutic strategies.
Our research focuses on ethical issues in medicine and life sciences. Some of our projects explore philosophical concepts such as vulnerability or altruism. For example, our team published a definition of vulnerability enabling more precise protections, which was integrated into the Declaration of Helsinki and the CIOMS guidelines. Others projects look empirically at morally relevant aspects of care, research, or health policy. For example, we conducted studies demonstrating the reality of physician bedside rationing in Europe, the US, and Ethiopia, and showing that discussions should focus on how, rather than on whether, it was practiced. We also explore concrete issues from a normative perspective with a view to developing applicable and justified solutions.
The lungs of cystic fibrosis patients are chronically infected by opportunistic pathogens. The links between the CF gene (CFTR) defect and the hyper-susceptibility of the CF lungs to stress and infection remains unclear. In this context, we are focusing on gap junctions, the junctional complexes that mediate the direct and regulated transfer of ions, metabolites and second messengers between cells. The regulation of these channels is defective in CF epithelial cells. Our aims are to unravel the intracellular signaling linking CFTR to gap junctions as well as their roles in host innate immunity and abnormal repair in response to infection.
Atherosclerosis and its clinical complications, such as arterial thrombosis, ischemia and myocardial infarction, continue to account for the majority of the morbidity and mortality of the adult population. Atherosclerosis is a progressive, multifactorial process that begins with the accumulation of lymphocyte and/or macrophage-type inflammatory cells in the intimal part of the vascular wall, followed by the proliferation and migration of smooth muscle cells. Our research group is interested in pro- and anti-inflammatory processes and molecules present during the atherogenesis. In different models we study also T and B cell subsets during the early and late stages of atherosclerosis. On another hand, we study the homeostasis of cholesterol through the regulation of LDLR by the endocytosis.
Our group is studying the mechanisms involved in human skeletal muscle regeneration, using an in vitro system. Skeletal muscle cells are large cells, plurinucleated and unable to divide. Following lesions, the tissue regenerate thanks to satellite cells, the adult muscle stem cells, that are normally quiescent but activate and proliferate as myoblasts after a lesion. This phase is initiated by the inflammation occurring upon injury. Once the inflammation decreases, the myoblasts stop proliferating and start to differentiate, fuse together and repair the damage. The mechanisms taking place during this process include a change of the membrane potential, the activation of calcium signals and transcription factors. Our aim is to understand the interplay between these mechanisms.
The research interests of our group focus currently on three major topics: (A) Study of adhesion molecules (junctional adhesion moelcule (JAM) family) and their role in homing and trafficking of normal hematopoietic cells as well as their role in lymphoma and leukemia development (B) Study of microvesicles, phenotyping and their role in the interaction between tumor cells and the microenvironment (C) Phenotypic analysis of hematopoietic stem cells and minimal residual disease detection in acute leukemia.
My laboratory works on reactive oxygen species-generating NADPH oxidases, as well as on stem cells as tools for disease models and cell therapy.
Our group studies chromosome segregation in human cells. We aim to understand how, during cell division, the components of the mitotic spindle, such as centrosomes, kinetochores, and microtubules, coordinate their function to establish a proper bipolar spindle and achieve faithful segregation of sister chromatids. Our interests focus on the fundamental molecular mechanisms controlling mitosis, how defects in these mechanisms lead to chromosome segregation errors in cancer cells, and how these errors can be exploited for anti-cancer treatments. Our studies rely on high-resolution quantitative light microscopy combined with chemical and genetic perturbations, cell biology, and biochemistry. Our group is part of the Translational Research Centre in Oncohematology.
Our projects study the contribution of unconventional antigen presenting cells, such as plasmacytoid dendritic cells or lymph nodes stromal cells, to peripheral T cell responses. Depending on the immune microenvironment, those cells can function either as tolerogenic or immunogenic antigen presenting cells. Our research aims at identifying and targeting new cellular functions to promote or in contrast inhibit T cell tolerance in the treatment of autoimmune diseases and cancer development, respectively.
The blood tissue consists of cells with various roles, involved in oxygenation of tissues or immunity. In mammals, these cells are constantly replenished in the bone marrow, from hematopoietic stem cells (HSCs). HSCs are multipotent and can self-renew. They derive from a small subset of HSCs produced during embryogenesis. Our main goal is to understand the molecular cues involved in HSC specification, expansion and differentiation. We use the zebrafish as a model to study HSC biology. Fertilization occurs externally, producing large number of embryos that can be easily manipulated. Importantly, zebrafish blood cells, as well as the molecular pathway necessary to their differentiation are conserved with other vertebrates therefore allowing us to translate our findings to the human model.
Our research group focuses on inflammatory processes in the central nervous system (CNS). Using model systems of human inflammatory brain diseases as well as human tissue samples, we investigate immunopathological processes in autoimmune inflammatory processes, as can be observed in multiple sclerosis. Furthermore, we investigate the formation and role of immunological memory cells in the context of viral infections of the CNS.
Malaria is a profound human health problem that kills almost half a million people each year. It is caused by parasites that replicate inside red blood cells and that can only be transmitted by mosquitoes. To time and adapt their development, malaria parasites use a complex system of intracellular signalling networks. We want to understand how signalling networks regulate the development and transmission of malaria parasites so that they can be targeted by new drugs.
The Geneva Centre for Emerging Viral Diseases, where I am based, is a joint institution of the University Hospitals of Geneva and the University of Geneva - with the aim to understand and prevent the spread of emerging and re-emerging viruses, by providing diagnostic capacity combined with clinical expertise and basic research. My research interests in particular are the laboratory-based risk assessment of zoonotic viruses. This includes the development of epithelial cell culture models from reservoir hosts such as bats and rodents and the assessment of viral diversity and virus discovery in both humans and animals. Further research interests are in the field of clinical virology, such as diagnostics for zoonotic viruses and assessment of imported virus infections.
Our aim is to understand how epigenetic information, in particular the 3D organization of human and mouse genomes instruct the development of organs and structures during embryogenesis. To map and functionally disrupt these chromatin states, we employ a variety of state-of-the-art technologies in pluripotent stem cells and in vivo during embryogenesis. The understanding of these basic concepts is critical to unravel the molecular mechanisms that underlie pathological gene misregulation in congenital malformations and cancer as well the mechanism that enable evolutionary novelties and diversity of life.
We study the mechanisms controlling the calcium and pH homeostasis of intracellular compartments, with a focus on innate immune cells. We showed that the store-operated calcium entry process mediated by STIM and ORAI proteins sustains the migration and bactericidal activity of phagocytic white blood cells. We now aim to decipher the molecular and ultrastructural determinants of the physiological calcium signals generated at sites of contact between the endoplasmic reticulum and phagocytic vacuoles. For this, we use mouse genetics, ion imaging, electrophysiology, electron microscopy, and a variety of imaging techniques.
The research focus of my group is to understand the pathophysiology of chronic kidney disease (CKD) and its complications. To this aim, we use animal models of kidney disease and proteinuria, but also patients samples including kidney biopsies and biological samples.Among current projects, the role of proteinuria on tubular cells is developped, linking proteinuria to fibrosis and cardiovascular complications. Modifications of oxygenation and tubular cell metabolism as factors of fibrosis progression are studied. Novel imaging techniques are developped in collaboration with the radiology department for early fibrosis detection. The goal of our translational approach is to determine new therapeutic pathways for CKD progression and complications, as well as novel diagnostic tools.
Motion is an intrinsic property of all living organisms and they have evolved diverse strategies to harness cytoskeletal proteins and motor proteins to organise cellular movement. The Apicomplexans are obligate intracellular parasites of considerable medical and veterinary significance that share a unique form of gliding motility, which is essential for their survival and infectivity. We are taking an integrated approach based on reverse genetics, biochemisty and live imaging to elucidate the molecular mechanisms and signaling cascades governing host cell invasion and egress from infected cells by Toxoplasma gondii. In parallel we investigate host-parasite interplays and cyst wall formation during parasite encystation, a process of central importance for pathogenesis and transmission
We study how lipid metabolism is organized in time and space, and contributes to the formation of molecular signatures that define organelle membranes or microdomains. Our goals are to understand how this three-dimensional organization is affected during ageing or in some human pathologies, e.g. Alzheimer. We develop original biochemical methods and integrate mass spectrometry, proteomics, lipidomics, microfluidics and bioinformatics to map cellular protein-lipid networks. Current work investigate the role in humans of largely unexplored networks of >100 lipid transfer proteins. How they mediate lipid movements across biological membranes, coordinate lipid metabolism between organelles and signal the (lipid) metabolic needs of each organelle.
Our research group focuses on the study and improvement of muscle regeneration and the treatment of osteoarthritis. Myogenic stem cell transplantation is a promising approach in the treatment of severe muscle damage as well as in the modulation of inflammation in osteoarthritic patients. We have 2 main areas of research. We want to better characterize, in vitro, human myogenic stem cells in order to improve their survival and their regenerative capacity after transplantation. We also want to study the anti-inflammatory capacities of these cells in experimental models of osteoarthritis in mice.
Pancreatic islets are characterized by a high number of heterotypic intercellular contacts between alpha and beta cells. Many studies indicate that cell interrelationships within islets are essential in the function of the endocrine pancreas. However whether and how direct contacts between alpha (secreting glucagon) and beta cells (secreting insulin) are involved in the hormonal secretion of these cells is poorly understood. The alpha and beta cells have a function per se in regulating glucose homeostasis, but through different mediators they secrete and/or via direct intercellular contacts may also regulate the function of the neighbouring cells. The major aim of our study is to investigate whether and how direct and/or indirect heterotypic contacts between alpha and beta cells contribute
Chronic infection by hepatitis B virus is a leading cause of cirrhosis and liver cancer in humans. By studying the regulatory HBx protein encoded by this virus, we found that the Smc5/6 complex, which has important roles in chromosome maintenance, also functions as a cellular restriction factor against hepatitis B and possibly other pathogenic viruses. It binds to the hepatitis B virus circular DNA genome and more generally to any episomal DNA to block transcription and, thus, viral infection. Hepatitis B virus counters this host defense by encoding the HBx protein that targets the Smc5/6 complex for destruction. We now wish to explore how the Smc5/6 complex detects and binds selectively to episomal DNA templates and not to chromosomal DNA and how, once bound, it silences transcription.
Our group has projects in two key sectors of primary care research: Clinical and health services research, and research in medical education. We prioritise themes in relation to daily ambulatory practice for which research conducted in hospital environments cannot provide responses. Our main research themes are (1) clinical and health services research: • High quality primary care services for young people • Pragmatic interventions for frequent disorders in primary care • Multimorbidity (2) Research in medical education • Increasing the proportion of medical students choosing a primary care career • Improving clinical teachers skills in primary care • Clinical reasoning (including clinical reasoning in the context of multimorbidity)
A human body is made of approximately 10^13 cells. All these cells arise through cell division starting from a unique cell, the fertilized oocyte. Cell division is therefore a crucial process that is required for an organism to grow. A specialized cell division, asymmetric cell division, contributes to cell differentiation, an essential process during development and in adult life. We study the processes of cell division and asymmetric cell division using human cells and the embryo of the roundworm Caenorhabditis elegans as model systems. We focus on understanding how cells are polarized and how the mitotic spindle, the structure the segregates the genetic material between daughter cells, is assembled and properly oriented during asymmetric cell division.
My group studies cancer-immune interactions that occur in the specialised microenvironment of the brain. We are exploring how hypoxia impacts on glioblastoma cells, which in turn can modify anti-tumour immunity through modified tumour cell surface phenotype, secretion of immunosuppressive cytokines, or direct communication with immune cells by release of extracellular vesicles. Both T cells and myeloid cells are being investigated as major immune players that can impact tumour progression. We are using new stringent mouse glioma models to test different immunomodulators together with cancer-targeting compounds in order to understand how best to combine different therapeutic modalities for future clinical application.
The syncytiotrophoblast (STB) is the outer layer of the foetal part of the placenta which is in direct contact with maternal blood. It is the main site of exchange for nutrients and gases between the mother and the fetus. Since their nuclei are not able to replicate, cytotrophoblast (CTB) fuse with overlying STB to bring fresh cellular components to the STB. To maintain homeostasis, apoptotic material of STB is packed into syncytial knots and then released into the maternal circulation. An increase in syncytial knots release could induce an inflammatory response by the mother and may lead to preeclampsia (PE), a major cause of maternal mortality and morbidity. Controlled CTB-STB fusion and trophoblast turnover are thus crucial to maintain the integrity of placental barrier.
Skeletal muscle dysfunction marks the decline of patient’s health condition in numerous pathological conditions. This often correlates with the loss of functional innervation of the tissue. The group focuses on the molecular network involved in the maintenance and plasticity of neuromuscular junctions in muscle. Specifically, we investigate the mechanisms regulating the expression and dynamics of synaptic proteins and the events triggering synaptic remodeling in muscle fibers. In translational projects, we further examine the processes threatening the neuromuscular system in specific disorders. We benefit from state-of-the art procedures to analyze signaling pathways and cellular processes in vivo using mouse models, in vitro using mature muscle cells, as well as in human muscle biopsies.
Bacterial cell envelope structures are important virulence determinants and targets of antibiotics. Many bacteria, especially members of the alpha-proteobacteria class, feature an overt cell cycle in which they trigger key events at pre-determined phases. In the model alpha-proteobacterium Caulobacter crescentus, several surface structures are periodically remodeled. While the underlying mechanisms are still incompletely understood, the synchronizeability of C. crescentus makes it a superb system in which to interrogate the temporal regulation of such dissimilar cellular components. To understand these mechanisms as well as how bacteria protect themselves from stresses imposed by antibiotics that target the cell envelope, we are using genetic, imaging and chemical (antibiotic) approaches.
We study circadian rhythms in the immune response using an interdisciplinary approach at the intersection of immunology, neuroscience and (patho)physiology. The recruitment of leukocytes to tissues and their localization within tissues plays a crucial role in the immune response. Recruitment of leukocytes to tissues underlies a circadian, i.e daily rhythm. This supports accumulating evidence for circadian oscillations in many components of the immune system. Specifically, the focus of our group is on how neural influences regulate the circadian migration of leukocytes to tissues, which promigratory factors control these rhythms and whether they can be altered by surgical, pharmacological or genetic interventions. The goal is to provide novel mechanistic insight into the systemic regulation
Immunoglobulin G (IgG) therapies are entering various clinical disciplines, most importantly the fields of oncology, transplantation and autoimmunity. Our current research focus in the general understanding of the mechanisms IgG-therapies; in particular, their effect on Natural killer (NK) cell mediated antibody-dependent cell-mediated cytotoxicity and monocyte (Mo) antibody-dependent cell-mediated phagocytosis.
Our overarching goal is to understand the rules of cell plasticity. Having worked extensively on early development, we now aim to understand how cells in primary tumors acquire metastatic fates. Currently the lab focuses on intercellular signaling and non-genetic changes that drive the acquisition of pro-metastatic states. We also explore the roles of embryonic signaling pathways in early steps of metastasis, investigating selected downstream targets and mediators.