Sean Cregan
Associate Professor
B.Sc. Cornell University
Ph.D. University of Ottawa, Cell Biology
Post-Doctoral Fellowship: Ottawa Health Research Institute
Office: Robarts Research Institute, Room 3244
p. 519.663.5777 x. 24134
f. 519.931-5789
e. scregan@uwo.ca, scregan@robarts.ca
Visit: Dr.Cregan at Robarts Research Institute
Why Science?
The idea of discovery has always appealed to me and I enjoy being able to continuously explore new ideas and ask new questions. During my undergraduate degree, I was primarily interested in biochemistry and cell biology, with an interest in pursuing a career in medical research. Prior to beginning graduate studies I worked at the Chalk River Laboratories where I developed a bioassay for monitoring radioactive iron (Fe55) uptake in nuclear workers involved in the re-tubing of nuclear plants. During my PhD supported by a scholarship from the CANDU Owners Group, I studied the effects of low dose radiation exposure on the sensitivity of human blood cells to undergo apoptotic cell death and its relation to cancer risk. When I moved on to do my post-doctoral fellowship, I decided to make the switch to study neurodegeneration; my expertise in looking at apoptosis and cell death pathways facilitated this transition, and I’ve focused on these topics ever since.
Research Goals
My lab focuses on studying molecular pathways that contribute to neurodegeneration to identify potential therapeutic targets for the treatment of stroke and neurodegenerative diseases like Parkinson’s disease. In individuals affected by these neurological conditions, brain cells degenerate and die through several programmed cell death pathways including apoptosis, ferroptosis and necroptosis. Therefore, we are investigating the signaling pathways that regulate these distinct programmed cell death pathways in the injured brain and are developing novel strategies to promote brain cell survival. We use transgenic animal models for in-vivo studies, primary cell-culture models (neurons, astrocytes and microglia), and recombinant viral vectors for cellular and in vivo manipulation of gene expression to guide our discoveries.
Specific Research Interests
1. The Role of BCL Family Proteins
The Bcl-2 gene family proteins are key regulators of mitochondrial integrity and cell survival. We have determined that the family members PUMA and BAX play a dominant role in promoting apoptotic death in neurons in diverse injury conditions. Therefore, we are currently investigating the molecular mechanisms involved in the activation of these proteins following injury and testing the ability of pharmacological inhibitors to prevent their activation in cell and mouse models.
2. Regulation of the Integrated Stress Response
The integrated stress response (ISR) is a cell signaling pathway activated in response to diverse types of stress. ATF4 is a central transcription factor that is activated by the ISR and induces the expression of genes that alter cellular metabolism and facilitate recovery. However, we have found that constitutive stress leading to sustained activation of ATF4 results in the activation of programmed cell death. Therefore, we are investigating the mechanisms by which ATF4 transitions from a pro-survival to a pro-death transcriptional program.
3. Neuron-Glia interactions in neurodegeneration
Neuroinflammation mediated by reactive astrocytes and microglia can affect neuronal function and survival in the injured/ diseases nervous system. We are investigating the signaling mechanisms involved in the activation of glia cells and how the altered secretome of these cells affects neuronal function and survival in primary cell culture and mouse models.
Most Rewarding Moments
I find discovering new information to be intrinsically exciting, and as you make more discoveries, it opens the door for new questions and a deeper understanding into the subject, as well as potential new applications. During my post-doc, I was one of two researchers to simultaneously identify apoptosis-inducing factor (AIF) as a key mediator of caspase-independent cell death in neurons. Getting my first CIHR grant was also a notable moment, as it provided me the opportunity to lead my own research team.
Awards and Recognitions
Please list the awards you’ve won from most recent to least recent in the following format if applicable:
Year Name of Award
2011 – 2016 Canada Research Chair
2009 – 2014 Early Researcher Award, Ontario Ministry of Research & Innovation
2006 – 2011 Canada Research Chair
2005 CIHR New Investigator Award
2002 CIHR Brain Star Award
2000 – 2003 CIHR Postdoctoral Fellowship
1999 – 2000 Heart & Stroke Foundation Postdoctoral Award
Publications
See my publications on Pubmed:
Highlighted Publications
- Demmings MD, Tennyson EC, Petroff GN, Tarnowski-Garner HE and Cregan SP (2021) Activating Transcription Factor-4 Promotes Neuronal Death Induced by Parkinson’s Disease Neurotoxins and α-Synuclein Aggregates (2021) Cell Death & Differentiation 28(5):1627-1643. org/10.138/s41418-020-00688-6 (PMID:33277577)
- Guadagno J, Swan P, Shaikh R and SP Cregan. (2015) Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells. Cell Death & Dis. Jun4;6e1779.doi: 10.1038/cddis.2015.151.
- Galehdar Z*, Swan P*, Fuerth B, Callaghan S, Park DS and Cregan SP (2010), Neuronal apoptosis induced by ER stress is regulated by ATF4-CHOP mediated induction of the BH3-only member PUMA. J Neurosci 30(50):16938-48.
- Khacho M, Tarabay M, Patten D, Khacho P, MacLaurin J, Guadagno J, Bergeron R, Cregan SP, Harper M-E, Park DS, and Slack RS (2014), Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival. Nat. Commun. 5:3550
- P. Cregan, A. Fortin, J.G. MacLaurin, S.M. Callaghan, F. Cecconi, S.W. Yu, T.M. Dawson, V.L. Dawson, D.S. Park, G. Kroemer, and R.S. Slack (2002), Apoptosis-Inducing Factor is Involved in the Regulation of Caspase-Independent Neuronal Cell Death. J. Cell Biol., 158 (3), 507-517.
