Main organizer and chair: Prof. Amalia Dolga
Timetable and information about the webinars can be found here.
13th of December 2023, 16-17:00 CET
Title of the talk: Development and application of in vitro, ex vivo and in silico models to assess placental transfer and effects of drugs
Abstract: The placenta plays a key role in maintaining a healthy pregnancy. To improve drug safety during gestation, it is relevant to understand to which extent and at which rate drugs are transferred across the placenta. While crossing the placenta, pharmaceuticals may also affect placental function. Pregnant women are not readily enrolled in clinical pharmacology trials, therefore data on drug efficacy and safety during pregnancy are scarce or become available only at a late stage after market introduction of a pharmaceutical. Translational pharmacology studies based on human tissues and cells are becoming increasingly important to fill this knowledge gap. In my talk I will highlight several ex vivo and in vitro models that we use to investigate the placental disposition and effects of small and large molecule pharmaceuticals, as well as how non-clinical pharmacokinetic data may be used in combination with physiology-based pharmacokinetic (PBPK) modeling to better understand clinical pharmacology during pregnancy.
Speaker 2: Dr. Manoe Janssen, Div. of Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, the Netherlands
Title of the talk: Advanced in vitro cell models to study genetic kidney diseases – An in vitro adventure
About Speaker: My research group is embedded in the group of Prof Dr Roos Masereeuw at the division of Pharmacy at Utrecht University. I specialize in the field of genetics and genetic disease, with a focus on genetic kidney diseases and lysosomal storage diseases. We use CRISPR/cas technology to develop new disease models and therapies. It is my ambition to improve the translational value of in vitro models and in this way contribute to the development of new therapies.
22nd of November 2023, 16-17:00 CET
Title of the talk: The Use of Stem Cell Models in a Drug Selection De-Risking Cascade
About Speaker: since I joined Janssen Pharmaceutica back in 2001, I’ve been involved in Safety Pharmacology and helped drug discovery-projects in their search of finding the best and safest drug-candidates to move this forward along the pipeline. The field of Safety Pharmacology differentiates on one end from Pharmacology in that it assesses unfavorable side effects of drug candidates and on the other end from Toxicology in that it looks for unfavorable physiological changes and not for direct structural tissue damage. This objective has an impact for the models, methods and strategy used. Within our team we apply in silico, in vitro and in vivo models in an integrated cascading fashion and look for complementary end-points across the models. Along my career the use of stem-cells models in de-risking strategies gained importance and at a certain point in time replaced a traditional animal-based pharmacology model. The learning curve, stepped approach, characterization (understanding opportunities and limitations) and decisions leading to this transition will be illustrated in this webinar.
Title of the talk: Effects of hibernation inspired modified 6-chromanol SUL-238 on vascular aging
Short summary:Vascular aging is marked by decreased vasodilation including lower nitric oxide (NO)– cyclic guanosine monophosphate (cGMP) –signaling. This can be partially and transiently compensated by endothelium-derived hyperpolarization (EDH) to avoid total loss of vascular function. Increased levels of reactive oxygen species (ROS) in the vasculature, believed to be produced by mitochondria, lead to loss of NO during aging. Both vasodilator pathways, NO-cGMP- and EDH-signaling, are potential drug targets to alleviate aging-related dysfunctions and targeting both would be an ideal mechanism for a new drug. The recently developed drug class of SUL-compounds, modified 6-chromanols, was shown to decrease ROS-production by inhibiting reverse mitochondrial electron transfer. In this talk, the effect of chronic treatment with the compound SUL-238 on vascular aging in mouse models will be discussed, highlighting NO-cGMP signaling, EDH signaling, and other aspects of vascular disease.
15th of March 2023, 16-17:00 CET
Title of the talk: Interventions in WNT signaling stimulate cardiac regeneration
Short summary: Myocardial infarction (MI) is a common cardiovascular event, frequently causing heart failure. This is due to cardiomyocyte loss and replacement by scar tissue in the infarct area, resulting in excessive dilatation of the ventricles. During normal wound healing after MI, the low rate of proliferation of cardiomyocytes in adult mammals prevents regeneration of the lost cardiac tissue, shifting the balance towards a massive fibrotic response. Therefore, investigations aiming to redirect the wound healing process away from scar formation, into the direction of cardiac regeneration have high scientific and societal potential. Interestingly, complete regeneration of the heart after injury has been demonstrated in zebrafish and newborn mice, underscoring its potential. Previous research has shown that multiple signaling pathways, including WNT signaling, are associated with the induction of cardiac regeneration in zebrafish and new-born mice. In the meantime, a rapidly growing body of literature has been published, showing the beneficial effects of interventions in WNT signaling in infarct healing in adult mammals. In this presentation, I will discuss the different pathophysiological mechanisms involved in infarct healing and the potential effects of interventions in WNT signaling on them.
Title of the talk: Drugging cell death to modulate inflammation
Short summary: Based in intensive care medicine, nephrology, and solid organ transplantation, Dr. Tonnus works on the delicate interplay of regulated cell death and inflammation. Whereas apoptosis was long seen as a synonym for regulated cell death, this nowadays encompasses various forms or regulated necrosis. Thus, necrosis became druggable raising new questions: Why so many pathways of regulated cell death? Why so complicated biochemistry to just get rid of a cell? Dr. Tonnus utilizes translational models of acute kidney injury to investigate the relative contribution of various forms of regulated necrosis such as necroptosis, ferroptosis, and pyroptosis and their inflammatory consequences. Whereas necroptosis and pyroptosis rely on enzymatic reactions to proceed, these are relatively easy to pharmacologically modulate. As ferroptosis relies on iron-dependent lipid peroxidation, this mode of cell death is particularly difficult to block in vivo. Here, Dr. Tonnus already demonstrated efficacy of different radical trapping agents in ameliorating acute kidney injury. Furthermore, he was involved in the development of the first combined inhibitor of both necroptosis and ferroptosis, Nec-1f. Dr. Tonnus aims to bring modulation of regulated cell death from bench to bedside.
15th of February 2023, 16-17:00 CET
Title of the talk: Driving the next generation of drug discovery for kidney diseases
Short summary:The next generation of treatments for kidney disease demands drugs that can achieve ever greater efficacy with the potential to stop disease processes, or maybe even cure them. This bold ambition requires a significant investment in research and development. In this talk you will learn about why we in AstraZeneca place great importance on scientific innovation together to drive drug development, and will highlight how we are using state of the art technologies and data resources to select the right therapeutic target for kidney disease. Time allowing, examples in small molecule and RNA approaches will show how we are developing novel pharmacological capabilities.
18th of January 2023, 16-17:00 CET
Speaker: Professor Elizabeth (Liesbeth) de Lange, Predictive Pharmacology research group, Division of Systems Biomedicine & Pharmacology at the LACDR, University of Leiden
Title of the talk: Predicting Drug Pharmacokinetics in the Central Nervous System – The Physiology-Based LeiCNSPK3.0 Mathematical Model and its applications
Short summary: Professor Elizabeth (Liesbeth) de Lange started researching neurotransmitters in fish brains at the Department of Neurology at the UMCG (then AZG) and graduated in Biophysical Chemistry at the University of Groningen. Her studies included a lot of mathematics and animal research. She then came to LACDR for her PhD research into a method for measuring brain concentrations as a function of time and location in laboratory animals: the microdialysis technique. Subsequently, this technique was further used and refined and brought many new insights into, among other things, the blood-brain barrier transport and brain distribution of drugs. This technique can be used to measure in human CNS, but this is highly limited by ethical restrictions, to only exceptional cases. The translation to humans must therefore take place via laboratory animal research and advanced mathematical modelling.
Liesbeth’s motto is that we cannot gain deep insights and make good predictions about complex situations if we use a simple approach. We need longitudinal and interrelated plasma and microdialysis data from different locations in the CNS in individual animals (smart data). This is complex and demanding, but necessary for the development of more general mathematical models that capture in-depth knowledge and insights. In addition, it contributes to the reduction and replacement of laboratory animals.
The Predictive Pharmacology research group (PI Liesbeth de Lange) continues to focus on CNS pharmacology and mathematical model development, but also on systems biology of rat Alzheimer’s disease using metabolomics and molecular biological techniques.
7h of December 2022
Speaker 1: Assistant Professor Sébastien Foulquier, Pharm.D., Dept. of Pharmacology- Toxicology, Maastricht University
Title of the talk: Hypoxic signaling in oligodendrocyte precursor
cells: relevance for cerebral small vessel disease
Short summary: White matter lesions are a hallmark of cerebral small vessel disease. Imaging studies have shown their association with decreased cerebral blood flow and increased blood brain barrier permeability. In this lecture, I will highlight the impact of hypoxia on oligodendrocyte precursor cells and how this may affect the cerebral small vessels.
Speaker 2: PhD student, João Faria, Dept. of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences
Title of the talk: Efficacy of mesenchymal stromal cells in ameliorating renal ischemia-reperfusion injury in vitro
Short summary: Kidney ischemia/reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). The current standard of care is focuse on treatments to support kidney function, stating the need for more efficient and specific therapies aiming to revert the injury. Mesenchymal stromal cells (MSCs) have been proposed as a novel cell-based regenerative therapy, showing promising results in several preclinical applications. However, its full potential in AKI is still unknown. In this talk, I will describe an in vitro model that can replicate key IRI features and discuss the role of MSCs in treating this type of injury.
16th of November 2022
Prof. Dr. F.J. Dekker, Chemical and Pharmaceutical Biology, University of Groningen
Title of the talk: Novelty for the old family of MIF proteins
Short summary: Many proteins are known for their function that was assigned to it upon its initial discovery. However, application of chemical-biological research methods enables identification of ‘novel’ roles for ‘old’ proteins. The lecture will highlight the identification of novel functions for the ‘old’ family of Macrophage migration Inhibitory Factor (MIF) proteins.
PhD student Alejandro Marmolejo-Garza, Molecular Pharmacology, University of Groningen
Title of the talk: Exposing mitochondrial involvement in Alzheimer’s Disease
About Speaker: Alejandro is an MPDI alumnus and is currently working under the supervision of Prof. Dr. Amalia Dolga, and Prof. Dr. Erik Boddeke. He focuses on the study of mitochondrial neurobiology in health and disease in the context of Alzheimer’s Disease. For his PhD project he explores the mitochondrial transcriptome and proteome, as well as the pharmacological targeting of mitochondrial mechanisms that impact neuronal viability and bioenergetics in vitro (iPSC-derived brain organoids) and in vivo.
29th of June 2022
Title: Precision Medicine in Respiratory Diseases
Abstract: Chronic respiratory diseases are multifaceted diseases. They comprise multiple phenotypes, which might benefit from treatment with different types of targeted therapies. Refining these phenotypes and understanding their underlying biological structure would help to apply precision medicine approaches. Using different omics methods, such as (epi)genomics, transcriptomics, proteomics, metabolomics, microbiomics, and exposomics, allowed to view and investigate respiratory diseases from diverse angles. In this talk I will give some examples of precision medicine approaches that are (hopefully) close to
implementation in clinic.
13th of April 2022
Speaker: Prof. dr. Laura Heitman, Professor of Molecular Pharmacology, Oncode Institute & Leiden Academic Centre for Drug Research (LACDR), Leiden University
Title: Targeting chemokine receptor CCR2 – From insurmountable antagonists to affinity-based probes.
Laura H. Heitman, PhD. is a full professor of Molecular Pharmacology at the Division of Drug Discovery and Safety at the Leiden Academic Centre for Drug Research (Leiden University), and at Oncode Institute. Her research interests are mainly focused on understanding and improving drug-receptor interactions, and more specifically, target binding kinetics and allosteric modulation of GPCRs and other membrane proteins, such as SLCs. She has obtained several competitive research grants, both personal and as part of consortia, all allowing her to study these novel, clinically relevant and highly translational concepts for drug action. Her research activities have currently led to an authorship on over 110 papers in this field, including one in Science (2012) and one in Nature (2016) with an H-index of 37. Lastly, she is the recipient of multiple awards (e.g. the ‘2017 MedChemComm Emerging Investigator’-award, runner up for the ‘2018 Prix
16th of March 2022
Title: Hibernation inspired drug development.
Rob Henning explores the molecular mechanisms enabling the miracles of mammalian hibernation: a repetitive, rapid and reversible reduction of metabolism by over 90%, leading to a drop in body temperature close to freezing. Endogenous production of H2S takes center stage in protecting cells from damage during hibernation dictated swings in physiology. He will explain why hibernators inspired the team to search for allosteric modulators of cystathionine beta synthase (CBS) and how they approach the discovery of this new drug class.
Speaker 2: PhD candidate Mohammed Saleh, Leiden Academic Center for Drug Research
Mohammed Saleh is a PhD candidate at Leiden Academic Center for Drug Research, working under the supervision of Prof. Liesbeth de Lange and Dr. Jeroen Elassaiss-Schaap. The focus of his PhD research is to develop mathematical models to predict the pharmacokinetics of central nervous system in healthy and of diseased conditions. Mohammed studied pharmacy in Egypt and did his master’s in pharmaceutical sciences at Utrecht University. In between, he gained experience on the drug industry at Novartis.
Title: LeiCNS-PK3.0: a framework leveraging multiscale data for accurate brain PK predictions
Abstract: Assessment of the unbound drug concentration in the central nervous system (CNS) is crucial for drug development to evaluate efficacy of CNS drugs and the safety of non-CNS drugs. Measuring the unbound drug concentration in the CNS target sites, i.e. brain cells and the surrounding extracellular fluid (brain ECF), is limited by ethical restriction of the human brain sampling, while lumbar cerebrospinal fluid (CSF) has been shown to be an inaccurate surrogate of the drug concentrations in the brain. The Leiden CNS pharmacokinetic predictor (LeiCNS-PK3.0) is a physiologically based pharmacokinetic model that was previously demonstrated to adequately predict the CNS PK profiles. LeiCNS-PK3.0 accounts mechanistically for the CNS physiology, a feature that allows interpopulation and interspecies translations of the PK profiles. In this webinar, we will explore the LeiCNS-PK3.0 model development and application to predict the brain PK profiles in Alzheimer’s patients.
16th of February 2022
Upon appointment as a Rosalind Franklin Fellow at the Groningen Research Institute of Pharmacy, she established a molecular neurobiology unit within the molecular pharmacology department. Her laboratory aims at identifying the molecular mechanisms responsible for cell death and at elucidating their involvement in human diseases.
Abstract: Progressive neurodegenerative diseases, including Alzheimer’s or Parkinson’s disease afflict millions of people worldwide. To address this unmet clinical need, it is important to gain more insight into the molecular mechanisms that drive neurodegenerative disease pathology. As mitochondrial dysfunction and inflammation are responsible for the initiation and progression of the neuropathology, proteins that prevent deregulation of both pathways are considered as drug targets. During this talk, I will discuss about mitochondrial dysfunction in iPSC-derived neurons from Alzheimer’s disease, and metabolic reprogramming in mouse microglia and human iPSC-derived microglia.
Experienced Science Director in Pharma Development. Skilled in strategic programs to prepare for IND and POC, with hands-on experience in Pharmacology (in-vivo/vitro, model development, mode-of-action profiling, safety pharmacology, and PK/PD projects), Translational Science & Biomarkers, Clinical Pharmacology MOA/safety studies) in different therapeutic areas. Strong science and experience basis, with >25 IND’s and >5 Marketing Authorizations, Lead positions in collaborations with academic and CRO partners. Proven management and leadershipqualities. Graduated from Leiden University (Pharm D) and Amsterdam University (PhD), and worked at Utrecht University (Veterinary pharmacology) before entering the Pharma business. 70+ scientific publications. Visiting scientist at Leiden University, LACDR.
Pharmacology in a company setting: contributions to ‘go/no go’ for drug selectivity in a translational science context; to MOA, and Biomarkers.
Abstract: Pharmacologists fulfil essential roles in drug development projects, no matter if the drugs are biologics or chemical entities. In a company setting there is always multidisciplinary teamwork in the non-clinical, and clinical context. Activity of a potential drug is always considered in the context of its safety and ADME properties in humans as the ultimate goal. This presentation will give examples of projects with specific ‘context’ problems and how these problems were overcome to get a clear ‘go’ or ‘no go’ for the project.
19th of January 2022
15th of December 2021
Title: Pharmacological targeting of nanocompartments in COPD and Alzheimer’s disease.
Abstract: Chronic diseases afflict millions of people of our worldwide aging society causing individual suffering and an enormous economic burden on our health care system. Chronic obstructive pulmonary disease (COPD) and Alzheimer’s dementia are common chronic diseases threatening the world population. COPD and Alzheimer’s dementia show tissue degeneration, inflammation and oxidative stress. Environmental stressors such as air pollutants and smoke are traditionally linked to COPD. Recent research had shown that people living in highly polluted areas have a higher risk in developing Alzheimer’s dementia. Despite the global impact of COPD and Alzheimer’s dementia, there have been very limited breakthroughs in our understanding and insights into the underlying mechanisms into their causes, treatment or cure. Clustering of cyclic nucleotide (and calcium) signaling in defined subcellular compartments/microdomains (signalosomes) has developed as a promising route to pursue to shed light into the mechanism enabling cells to exert their highly specialized tasks. Drugs used to alleviate COPD and Alzheimer’s dementia symptoms are beta-agonists and phosphodiesterase (PDE) inhibitors. The molecular drug targets of these drugs – beta-adrenergic receptors and PDEs – are key players in compartmentalization. Our research team enrolled unconventional compartment players such as A-kinase anchoring proteins and exchange proteins directly activated by cAMP, and yet to be further characterized targets. We showed that endogenous signaling properties of these multi-protein complexes define drug action – processes being disturbed under disease conditions. To increase the probability to reprogram these multi-protein complexes and to subsequently restore their cellular function, we used approved drugs in combination with novel druggable components to achieve direct pharmacological targeting of nanocompartments. Our concept potentially not only holds for COPD and Alzheimer’s dementia but also for other chronic diseases.
I reach out to colleagues – both at university and company settings – to share knowledge, tools and compounds to develop novel compartmentalized treatment strategies.
Supervisors: Prof Amalia Dolga and Prof. Wilfred den Dunnen
Title: Underlying mechanisms of ferroptosis in Alzheimer’s disease.
Abstract: Alzheimer’s disease (AD), the most common form of dementia, currently affects 40–50 million people worldwide. Despite the extensive research into amyloid β (Aβ) deposition and tau protein hyperphosphorylation (p-tau), an effective treatment to stop or slow down the progression of neurodegeneration is missing. Emerging evidence suggests that ferroptosis, an iron-dependent and lipid peroxidation-driven type of programmed cell death, contributes to neurodegeneration in AD. Therefore, how to intervene against ferroptosis in the context of AD has become one of the questions addressed by studies aiming to develop novel therapeutic strategies. However, the underlying molecular mechanism of ferroptosis in AD, when ferroptosis occurs in the disease course, and which ferroptosis-related genes are differentially expressed in AD remains to be established. Our objectives are to 1. analyze which ferroptosis-related genes are differentially expressed in AD brain dependent on cell type, disease progression and gender, and 2. to compare the expression of ferroptotic markers between a) white and grey matter, b) Aβ versus non Aβ areas containing areas and c) high p-tau versus low p-tau-related areas of human post-mortem brains. Future studies should focus on developing new tools able to demonstrate where and when cells undergo ferroptosis in AD brain and build more translatable AD models for identifying anti-ferroptotic agents able to slow down neurodegeneration.
10th of November, 2021
Title: Modeling of vascular aging and drug target identification with DNA repair mutant mice.
Aging is the single largest cause of disease in economically advanced societies. Cardiovascular disease is strongly represented in this context. Non-atherosclerotic vascular aging is a growing topic, its implications in health and life span being increasingly appreciated. This used to be a problematic filed of research due to the lack of convenient methods. In recent years I have developed mouse models to explore this type of vascular aging, namely by partial inactivation of DNA repair in vascular cells. Persistent activation of DNA damage response leads to accelerated development of aging features independently from the presence of risk factors. In my presentation I will illustrate how this impacts cardiovascular function in comparison to the typical risk factor-induced problems. Also, I will show how my lab has identified relevant drug targets using accelerated vascular aging mice.
Very recently I have developed an interest in redox regulation, and I am trying to develop this as a research line, again placing drug development center stage. My lab does not have all the required experience and facilities to examine important aspects of redox regulation, and I kindly invite anyone skilled for collaboration. Furthermore, we are collecting tissues continuously and I would be happy to share tissues with anyone who is interested.
7th of July, 2021
Prof Reinoud Gosens, Department of Molecular Pharmacology, University of Groningen
Title: Pharmacological targeting of tissue remodeling and repair in the respiratory tract.
My current research interests are focused on mechanisms that regulate structural remodelling and repair of the airways and lung parenchyma in asthma and COPD. Identifying novel therapeutics for chronic lung disease is my long-term scientific goal. In this endeavour, I focus my work on the one hand on asthmatic airway remodeling, and in particular on the regulation of this pathological process by cholinergic receptors and the airway cholinergic system. Using in vivo and in vitro models the aim is to unravel the muscarinic receptor subtypes and signaling involved. Moreover, we are interested in the mechanisms that regulate plasticity of the airway neural network in asthma for which we recently established stem cell-derived airway cholinergic neurons. A second focus of my work is regenerative pharmacology of the distal lung in COPD and IPF. Here, my research interests are mainly centered around the function and dysfunction of distal lung stem cells/progenitors in health and disease. In particular, I am interested in understanding progenitor cell-niche interactions in disease as a potential background for the discovery of novel drug targets. In my presentation, I will shortly discuss both research lines and invite collaboration in each of these areas.