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The mechanisms underlying adverse effects of pharmaceuticals

Development of an AOP for cardiotoxicity mediated by the blockade of L-type calcium channel

Calcium ions play a vital role in cellular and organism physiology. A diverse set of calcium channels contribute to the timely regulation of calcium currents at a cellular level. Among them, the L-type calcium channel is responsible for the excitation-contraction coupling of skeletal, smooth, and cardiac muscles. Pharmaceuticals that unintentionally block this channel in cardiac cells may impair heart function and health, leading to various cardiac pathologies and predisposing individuals to heart failure.

Advancing our understanding of the mechanisms underlying those adverse effects is of paramount importance if we want to develop effective strategies able to accurately predict potential cardiotoxicity as early as possible during drug development. The aim of this project is to develop an Adverse Outcome Pathway (AOP) that describes the series of causally related key events triggered by the blockade of L-type calcium channel, and that can ultimately lead to heart failure. This AOP will represent a valuable knowledge base able to guide the identification of key events that are highly predictive of in vivo toxicity, and that can be measured in vitro without relying on animal testing.

The knowledge base will also be used as a platform to drive future development projects aimed at incorporating additional layers of complexity in the model, and at driving the transition towards a fully quantitative AOP able to effectively support decision-making.


Meet the Principal Investigator(s) for the project

Dr Luigi Margiotta-Casaluci - Luigi is a Lecturer in Pharmacology and Toxicology, and Group Leader in the Department of Life Sciences, Centre of Inflammation Research and Translational Medicine. He is specialised in the quantitative bi-directional extrapolation of complex biological processes between zebrafish, pre-clinical mammalian species, and humans. His research focuses on understanding the multi-scale effects of pharmaceuticals, alone and in combination, and developing predictive models able to support drug safety assessment. In parallel with the drug safety research, Luigi is also interested in understanding the molecular mechanisms underlying specific behavioural phenotypes. The Margiotta-Casaluci Lab is currently using the zebrafish model to study the effects of chronic inflammation on brain and behaviour. This research aims at generating novel mechanistic understanding that can potentially support the identification of more effective therapeutic strategies for patients affected by behavioural disorders. Since starting his independent group in 2015, Luigi secured external research funding as Principal Investigator from several public research councils (e.g. BBSRC, NC3Rs, European Commission) as well as industrial partners (e.g. AstraZeneca). His current research includes the following projects:  (2017-2021; BBSRC/AstraZeneca): Understanding molecular and phenotypic effects of cyclo-oxygenase inhibition in the zebrafish model.  (2017-2018; NC3Rs): Development of an Adverse Outcome Pathway for cardiotoxicity mediated by the blockade of L-type calcium channels.  (2018-2021; Brunel Isambard Award): Understanding the effects of chronic inflammation on brain and behaviour.  (2019-2022; H2020 European Commission): GOLIATH: Generation of novel, integrated and internationally harmonised approaches for testing chemical-induced metabolic disruption. Career 2020-to date: Group Leader & Lecturer, Pharmacology & Toxicology, College of Health and Life Sciences, Brunel University London, UK 2018-2020: Group Leader & Research Fellow II, Comparative Pharmacology & Toxicology, College of Health and Life Sciences, Brunel University London, UK 2015-2018: Group Leader & Research Fellow, Comparative Pharmacology & Toxicology, College of Health and Life Sciences, Brunel University London, UK 2011-2013: Visiting Scientist, AstraZeneca, UK 2011-2015: Post-doctoral Research Fellow, AstraZenenca/Brunel University London, London, UK (funded by BBSRC/AstraZeneca). Education 2007–2011: Ph.D. in Environmental Toxicology, Brunel University London, London, UK (supported by GlaxoSmithKline) 2003-2005: MSc Marine Biology, Universita’ Politecnica delle Marche, Ancona, Italy 2000-2003: BSc Biological Sciences, Universita’ Politecnica delle Marche, Ancona, Italy

Related Research Group(s)

Inflammation Research and Translational Medicine

Inflammation Research and Translational Medicine - Interdisciplinary research into understanding the inflammatory and immune processes that underlie human health, disease and healing.


Project last modified 15/07/2021