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Leiden University Medical Center

ACADEMISCH ZIEKENHUIS LEIDEN
Country: Netherlands
169 Projects, page 1 of 34
  • Open Access mandate for Publications and Research data
    Funder: EC Project Code: 834513
    Overall Budget: 2,233,250 EURFunder Contribution: 2,233,250 EUR
    Partners: Leiden University Medical Center

    Due to a significant increase in the use of artificial light in our 24h economy, the biological clocks of all living organisms, including humans, are severely disrupted. Many severe health disorders are consequences of clock disruption such as diabetes, sleep/mood disorders, cardiovascular disease, and immune dysfunction. The central timekeeper in mammals is the suprachiasmatic nucleus (SCN), and the mechanisms by which light disrupts integrity of the SCN has been well investigated in nocturnal species. In contrast, mechanisms of clock disruption in humans and other diurnal (day-active) species remain poorly defined. I have evidence that the mechanisms that drive SCN function are fundamentally different between nocturnal species and diurnal species. This defines my aim to restore proper clock function in diurnal species, including humans. To test this, in Objective 1 we will identify similarities and differences between nocturnal and diurnal clocks with respect to their i) response to light, ii) neuronal synchronization, iii) output, and iv) response to physical activity. Based on these findings, in Objective 2 we will develop novel strategies to manipulate and restore clock function in diurnal species. These objectives will be achieved using novel, state-of-the-art chronobiology methods including in vivo electrophysiology and Ca2+ and bioluminescence reporters—all in freely behaving day-active animals, as well as in slice preparations containing the SCN. For studies on the human SCN we record with 7-Tesla fMRI. This proposal will help establish a new basis for chronobiology with respect to the most suitable models for studying translational applications. The results will yield immediate benefits in terms of manipulating biological clock function among vulnerable populations in modern society, particularly the elderly, patients in intensive care, and shift workers.

  • Open Access mandate for Publications and Research data
    Funder: EC Project Code: 891670
    Overall Budget: 187,572 EURFunder Contribution: 187,572 EUR
    Partners: Leiden University Medical Center

    The anaphase promoting complex/ cyclosome (APC/C) is an E3 ubiquitin ligase that controls the cell division cycle by targeting main cell cycle regulators for proteasomal degradation, thereby ensuring error-free cell division and safeguarding genome stability. Its foremost activity is during cell division, or mitosis, when two sets of sister chromatids are equally divided over two newly formed daughter cells. Intriguingly, APC/C substrates that are degraded at the metaphase-to-anaphase transition have binding partners, which are not degraded. It remains a mystery how the APC/C controls degradation of the substrates and leaves the binding partners undisturbed. My objective is to clarify the molecular mechanism of substrate-binding partner disengagement, and determine the impact of disengagement on substrate degradation, to ensure controlled sister chromatid separation and genome integrity. First, I propose to identify the precise timing of disengagement during the process of ubiquitination, at the molecular level: this will give fundamental insight into disengagement control (Objective 1). Next, I will study ubiquitination at the proteomics level, by unraveling how Lysine-choice, and ubiquitin chain topology affect disengagement (Objective 2). Finally, I will combine conventional molecular biology methods with advanced microscopy techniques to investigate the importance of controlled substrate-binding partner disengagement for substrate degradation and genome stability (Objective 3). I will employ a multi-disciplinary approach, combining molecular biology, proteomics, and in vivo cell biology approaches to resolve this fundamental biological question. The identified mechanism may provide insights into ternary complex formation of the APC/C and its substrates, which will enable translation to develop targeted-protein-degradation drugs.

  • Open Access mandate for Publications and Research data
    Funder: EC Project Code: 838985
    Overall Budget: 187,572 EURFunder Contribution: 187,572 EUR
    Partners: Leiden University Medical Center

    The incidence of cardiac arrhythmias in Europe is increasing because of aging and unexpected side effects of drugs, such as chemotherapeutics. To understand mechanisms underlying these conditions requires reliable preferably human models. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are presently good candidates since they share the genome of the individual from whom they are derived and can thus recapitulate genetic, ethnic and gender contributions to the cardiac disease phenotypes. However, their immature state and high inter- and intra-line variability is limiting their value as preclinical models. In the proposed project, I will address these issues through an interdisciplinary approach combining a unique 3D culture maturation system developed in my host lab with my expertise in electrophysiology. I will characterize gene expression and electrical properties of single cardiomyocytes simultaneously with view to directly correlating genes with function and identify molecular markers associated with the functionally mature cardiac phenotype. Two genetic cardiac diseases (one caused by an imprinted gene, the other by a postnatally expressed splice variant) for which the host already has hiPSC lines, will be used as proof of concept that hiPSC-CM maturation in this system is sufficient (i) to reveal disease phenotypes not evident in conventional culture and (ii) to identify molecular markers suitable for selecting mature hiPSC-CMs for drug testing. Overall, this project will provide the first functionally-relevant gene signature of (mature) hiPSC-CMs, and thus be an important advance in modelling all cardiomyocyte autonomous cardiac diseases more precisely for (personalized) drug screening. The outcome will be available to academic and private researchers to enhance rates of drug discovery and safety, and promote hiPSC-CMs as validated adult cardiac models to replace, at least in part, the use of animal models.

  • Open Access mandate for Publications
    Funder: EC Project Code: 101021218
    Overall Budget: 2,493,720 EURFunder Contribution: 2,493,720 EUR
    Partners: Leiden University Medical Center

    MRI is a key modality in clinical care, with well over 150 million scans performed annually for diagnosis and treatment monitoring. Its major strengths are multi-contrast and the lack of ionizing radiation. However, its Achilles-heel is cost: typically millions of euros to purchase, site, and maintain, and also requires highly skilled technicians. As a result, MRI is available only in larger hospitals in the developed world, and unlike other imaging modalities plays little role in population screening. In the developing world, MRI systems are far too expensive and complex to purchase and maintain, and over 70% of the world’s population has zero access to MRI, which could be critical in treating diseases such as hydrocephalus, stroke, head trauma and viral infections. The aims of PASMAR are to develop new low-field MRI systems which will enable a role in medical screening in the developed world, as well as providing an affordable, sustainable and accessible platform for the developing world. The major thrust of PASMAR is methodological, designing new types of low-cost low-field systems for specific clinical applications, and optimizing all aspects of system performance to overcome the challenge of much lower MRI signal. I aim to develop, in consultation with clinical colleagues locally and via ongoing collaborations with engineers and clinicians in Africa, specialized systems which can be used for adult/pediatric brain, orthopedics and lung/spine scanning, as well as new types of inexpensive handheld ultra-lightweight surface scanners. These take advantage of the enormous flexibility of designing permanent magnet arrays with completely new geometries, targeted for specific organs. I will focus on portability to maximize patient reach and minimize siting requirements, accessibility via dramatically reduced system costs, and sustainability via modular and open source design to allow local maintenance and repair.

  • Open Access mandate for Publications
    Funder: EC Project Code: 724517
    Overall Budget: 1,999,800 EURFunder Contribution: 1,999,800 EUR
    Partners: Leiden University Medical Center

    In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed. Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions: 1) What is the physiological function of complement binding to PTM proteins? 2) Is the breach of tolerance towards PTM proteins influenced by complement? 3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity? With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.