Sean P. Cregan, PhD

Scientist, Cell Biology Research Group, Robarts Research Institute
Researcher of the month: 
Aug 2010

The intricacies of cell suicide fascinate Dr. Sean Cregan. With his research team in the Cell Biology Laboratory at Robarts Research Institute, he searches for the agents of death – the molecules that force injured nerve cells in the brain to die during stroke or in neurodegenerative conditions, such as Parkinson’s, Alzheimer’s and Huntington’s disease.

Normal cells commit suicide, a process called apoptosis, when they become disordered or unnecessary. Stroke injury and brain diseases can use signaling mechanisms naturally embedded within brain cells to trigger their untimely death.

“I’m interested in identifying the molecules that determine whether neuronal cells live or die in these conditions,” says Dr. Cregan. Once identified, he hopes that he and other researchers can develop drugs to target these loaded guns to keep neurons alive.

Apoptosis is a complicated process. Within cells, many molecules can activate a cascade of signalling events that eventually trigger suicide. Like lightning, these signals can travel along different pathways to reach ground zero. Proteins along these redundant corridors work in what seems like confounding and mysterious ways to ensure that self-destruction occurs.

Scientists like Dr. Cregan are only now beginning to identify these deadly triggers. Their challenge is to find the key regulators of unique cell-signalling pathways that send the kiss of death to neurons in different brain conditions. If successful, they may be able to stop unwanted or inappropriate cell death in its tracks.

A Montreal native, Dr. Cregan studied biochemistry at Cornell University on an academic and hockey scholarship. He completed his postgraduate work at the University of Ottawa, where he developed his understanding of signaling mechanisms in cell death while working on his thesis at the Chalk River Nuclear Laboratories.

In 2002, as a postdoctoral fellow at the Ottawa Health Research Institute, he received the Canadian Institutes of Health Research (CIHR) Brain Star Award, which recognizes the excellence of neuroscience research in Canada.

Dr. Cregan was one of the first scientists worldwide to identify the key role of apoptosis-inducing factor (AIF), an atypical regulator of cell death in the brain. His work has sparked interest in several laboratories to examine the role of AIF in brain injury during stroke.   

“It’s always nice to be productive as a postdoctoral fellow,” he says, “but the ability to successfully obtain funding to support my own research team as an independent investigator was a highlight for me.”

In 2004, Dr. Cregan became an independent scientist at the Robarts Research Institute. He is a Canada Research Chair and CIHR New Investigator. Last year, he received the Ontario Early Researcher Award. The Heart & Stroke Foundation also funds his research.

Finding PUMA

At the Robarts Research Institute, Dr. Cregan studies the BCL-2 family of genes, which activate within cells to trigger apoptosis in different injury conditions. “If you inhibit one of them, you probably won’t prevent cell death from occuring,” he says, “because there’s a lot of redundancy in these proteins.”

From his experiments, he discovered that one gene seems to be essential for programmed cell death in many brain conditions. This gene is p53 up-regulated modulator of apoptosis (PUMA). He found that deleting PUMA from neuron cells dramatically affected their ability to commit suicide.

“PUMA is one of the key players in regulating neuronal apoptosis. We know that its expression seems to be nonexistent under normal conditions but activates in injury conditions,” he says.

“The signalling processes that induce PUMA seem to be quite distinct in different injury and disease conditions, but we’ve found evidence in animal models that PUMA seems to be one of the key downstream targets in all of these cases.”

Dr. Cregan and his colleagues are now studying ways to interfere with the expression of PUMA during gene transcription. Cell-culture models, DNA microarrays and mass spectrometry are the basic tools in his technically advanced research kit. He believes that refinements in this technology will give scientists a strong ability to answer questions about brain injury in years to come.

For further information, please contact Sean P. Cregan, PhD using the Email contact form or by phone at 519 931-5777 ext 24134