Discovery and validation of new ceramide synthase inhibitors to treat metabolic disease

Summary

Ceramide synthase enzyme isoforms 1, 5, and 6, are heavily implicated as drivers of obesity, insulin resistance, and diabetes. Targeting these enzymes is expected to yield new therapeutics for the treatment of these conditions. This project involves the discovery and full biochemical characterisation of new chemical compounds that inhibit specific members of the ceramide synthase enzyme family.

Supervisor(s)

Associate Professor Anthony Don, Dr Jacob Qi

Research Location

Camperdown - Charles Perkins Centre

Program Type

Masters/PHD

Synopsis

The ceramide synthases are a family of enzymes that catalyse synthesis of the lipid ceramide, which is heavily implicated in the pathogenesis of obesity, insulin resistance, and diabetes. In mammals there are six ceramide synthase isoforms (CerS1-CerS6), each of which exhibits a specific preference for synthesis of particular forms of ceramide. CerS1 is expressed exclusively in the brain and skeletal muscle, where it catalyses synthesis of the C18 form of ceramide. CerS5 and 6 catalyse the synthesis of C16 ceramide, and are believed to mediate insulin resistance and other adverse metabolic effects in the liver and adipose tissue. Recent research has demonstrated that C18 ceramide is increased in the skeletal muscle of obese individuals, and decreases with exercise.

There are currently no isoform-specific ceramide synthase inhibitors. My research team has now developed the first potent and selective inhibitor of the CerS1 enzyme. This inhibitor was found to have potent effects in reducing fat deposition and weight gain in mice fed a high fat diet. Our current data indicates that this effect is mediated through enhanced oxidative metabolism of fatty acids, thereby reducing fat storage.

In this project you will screen for, develop, and characterise new ceramide synthase inhibitors, specifically aiming to develop inhibitors of the ceramide synthase 5/6 isoforms. New inhibitors will be tested both in vitro, in cell culture models, and in mouse models of high fat feeding and obesity.

Alternatively, you will further characterise our world-first CerS1 inhibitor, specifically determining (1) if this inhibitor can accelerate the "burning" of existing fat stores, and (2) the biochemical pathways through which ceramide synthases (particularly CerS1) regulate fat levels.

This project is suitable for anyone with anyone with a chemistry, biochemistry, molecular biology, or medical science background.

Additional Information

I run a focused and supportive research team including students, postdocs, and a research assistant. You will have plenty of support for your PhD studies, and access to the most sophisticated equipment and resources.A top-up payment of $6000 will be made for any candidates who have their own scholarship. For those candidates with a good first class or high scoring second class honours who have not received a competitive government scholarship, please see me and I will discuss the possibility of funding a scholarship.

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Keywords

Metabolic disease, Insulin resistance, diabetes, Lipid, metabolism, Obesity, Pharmacology, drug discovery, chemistry, Charles Perkins Centre

Opportunity ID

The opportunity ID for this research opportunity is: 2369

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