Dr Luigi Margiotta-Casaluci
Visiting Senior Lecturer - Life Sciences

Research area(s)

ONGOING RESEARCH PROJECTS

Understanding molecular and phenotypic effects of cyclo-oxygenase inhibition in zebrafish

BBSRC/AstraZeneca Industrial Case PhD Studentship 

The aim of this project is to gain new insights into the fundamental biology of prostanoids by investigating the molecular and phenotypic effects of cyclo-oxygenase inhibitors in zebrafish. Non-steroidal anti-inflammatory drugs (NSAIDs) are used by millions of people worldwide every day to treat a wide variety of conditions that involve pain, fever and inflammation. These compounds act by inhibiting one or both isoforms of the enzyme cyclo-oxygenase (COX), which catalyse the synthesis of prostanoids. Major advances have been made in our understanding of NSAIDs pharmacology and toxicology; however, many aspects of the biological significance of COX inhibition still remain poorly understood. In this project, we twill focus on the effects of cyclo-oxygenase inhibitors on immune and gastro-intestinal system of zebrafish and will explore the interplay between the two responses.

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

NC3Rs Strategic Award 

Calcium ions play a vital role in cellular and organism physiology. These ions are a central component of a complex system of intracellular messengers that mediates a wide range of biological processes. A diverse set of calcium channels contribute to the timely regulation of calcium currents at cellular level. Among them, the L-type calcium channel is responsible for the excitation-contraction coupling of skeletal, smooth, and cardiac muscle. 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 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.

GOLIATH - Generation Of Novel, Integrated and Internationally Harmonised Approaches for Testing Metabolism Disrupting Chemicals

H2020 - Eurpean Commission  

GOLIATH focusses on one of the most urgent regulatory needs in the field of endocrine disrupting chemicals, namely the lack of methods for testing EDCs that disrupt metabolism – chemicals collectively referred to as ‘metabolism disrupting chemicals’ (MDCs). MDCs are natural and anthropogenic chemicals that have the ability to promote metabolic changes that can ultimately result in obesity, diabetes and/or fatty liver in humans. GOLIATH will generate the world’s first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. With a focus on the main cellular targets of metabolic disruption – hepatocytes, pancreatic endocrine cells, myocytes and adipocytes – GOLIATH will develop new methods and optimise existing methods that span the entire adverse outcome pathway (AOP) spectrum, using in silico predictive modelling and high throughput screening, (pre-)validated ready-to use in vitro assays and optimised in vivo toxicity testing guidelines. GOLIATH will provide key information on the endocrine mode of action by which MDCs disrupt metabolic pathways and induce adverse effects on human health by incorporating multi-omics technologies, and translating results from in vitro and in vivo assays to adverse metabolic health outcomes in humans at real life exposures. 

Research Interests

Drug safety, zebrafish, comparative pharmacology and toxicology, inflammation, cardiotoxicity, multi-scale modelling, PK/PD modelling, adverse outcome pathway (AOP), pharmaceuticals in the environment 

Grants