Main organizer and chair: Prof. Amalia Dolga
Timetable and information about the webinars can be found here.
13th of April at 16:00-17:00 CET
Meeting ID: 873 9134 0982
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 at 16:00-17:00 CET
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 at 16:00-17:00 CET
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 at 16:00-17:00 CET
15th of December at 16:00-17:00 CET
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.
Wednesday 10th of November, 17-18:00 o’clock
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, 17-18:00 o’clock
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.