The Molecular Signaling Laboratory focuses on the effects of two important and interrelated aspects of heart development: molecular regulation of myocyte differentiation and regeneration.
The first research objective is the elucidation of the role that A-type lamins play in cellular differentiation and repair in the normal and diseased heart (funded by the Canadian Institutes of Health Research and the Heart and Stroke Foundation).
The second objective concerns the dissection of general molecular mechanisms of cell cycle regulation and signalling during perinatal heart development and how those genes are involved in growth and differentiation of the normal and diseased heart (funded by the JP Bickell Foundation).
Cardiac Manifestation of Laminopathies
We discovered that MLIP, a single-copy unique gene found only in amniotes (birds, reptiles and mammals), provides the first direct molecular link between the lamin A/C and gene expression. MLIP may account for the role lamin A/C plays in cellular differentiation, development and aging. This strongly suggests that MLIP lies in a prominent position in the regulatory tree of differentiation and development. The objectives of the experiments proposed within this project are to further elucidate the in vivo and molecular function of MLIP during LMNA-associated pathogenesis of cardiac degenerative disorders and aging. The functional identification of MLIP is an important advancement to the broad fields of cellular and developmental biology. We have generated all the MLIP models and molecular tools, allowing us to further define the biological role of MLIP. These tools include a characterized and validated MLIP-specific antibody, MLIP-specific shRNAi sequences, and a newly established conditional MLIP knockout model.
The human heart’s ability to regenerate is lost during the perinatal transition, when cardiomyocytes exit the cell cycle shortly after birth. During the onset of pathological hypertrophic or dilated cardiomyopathies post-myocardial infarction (post-MI), a number of the fetal heart genes are reactivated, yet there is no evidence of adult cardiomyocyte re-entry into the cell cycle. Both humans and mice display post-MI remodeling differences between young and elderly adults. These differences translate into a less effective myocardial repair, greater infarct expansion, and poorer prognosis in the elderly. Despite the importance of this phenomenon, little is known about the molecular basis for the reactivation of the fetal genes in the post-MI heart.
Micro-RNAs (miRNAs) play an essential role in global regulation of gene expression, with a single miRNA estimated to modulate as many as 200 different genes. miRNAs are expressed in the heart and have been demonstrated to regulate cardiac development and growth. miRNA involvement in cardiac remodelling and repair mechanisms remains largely unknown. We propose that miRNAs play a key role in the acute regulation of cardiac gene expression during the normal transition from a fetal heart to the adult heart as well as in the post-MI heart.
The objective of this project is to define mechanisms that control cardiac cell division and hypertrophy with a view to identify molecular cues that control fetal gene reactivation post-MI and subsequent re-entry of cardiomyocytes into the cell cycle.
Physiologically and pathophysiologically, our elucidation of the molecular mechanisms and pathways that are essential for normal myocardial transition from hyperplastic to hypertrophic growth during the perinatal period may provide important molecular information about myocyte cell cycle control and terminal differentiation.
- Jiang J*, Burgon PG*, Wakimoto H*, Onoue K*, O’Meara C, Fomovsky G, McConnell BK, Lee RT, Seidman JG and Seidman CE. Cardiac Myosin Binding Protein C Regulates Postnatal Myocyte Cytokinesis. 2015 PNAS (In Press) *equal contribution
- Burgon, PG*, Human genome organization-symbolized muscle-enriched a-type lamin-interacting protein to clear up confusion. Circ Res. 2012 Oct 12;111(9):e252.
- Ahmady E, Deeke SA, Rabaa S, Kouri L, Kenney L, Stewart AF, Burgon PG. Identification of a novel muscle enriched A-type lamin interacting protein (MLIP). Journal of Biological Chemistry. 2011; 286(22): 19702-13.
- King JC, Moskowitz IP, Burgon PG, Ahmad F, Stone JR, Seidman JG, Lees JA. E2F3 plays an essential role in cardiac development and function. Cell Cycle. 2008 Dec 22;7(23).
- Burgon PG, Lee WL, Nixon AB, Peralta EG, Casey PJ. Phosphorylation and nuclear translocation of a Regulator of G-protein Signaling (RGS10). Journal of Biological Chemistry. 2001; 276 (35): 32828-34.
A key component of the Molecular Signaling Laboratory’s research mission is the training of students and postdoctoral fellows in all aspects of research, enabling them to become outstanding future scientists.
Current Team Members
Esther Mak, BSc, MSc
Jonathan Weldrick, BSc Hons
Burgon Lab Alumni
Elmira Ahmady, BSc Hons, MSc, DDS
James Broughton, BA
Marie-Elodie Cattin, PhD
Shelley Deeke, BSc Hons, MSc
Ruxandra Gheorghe, BSc Hons (University of Toronto)
Jennifer Kasbary, BSc Hons
Laura Kenney, BSc Hons, MSc (Health Canada)
Lara Kouri, BSc Hons, MSc
Stanimira Krotneva, BSc Hons MSc (Erasmus University, Rotterdam)
Nika Maani, BSc Hons
Amy Mullins, BSC Hons
Seham Rabaa, BSc Hons, MSc
Fawaz Saleh, BSc Hons, MSc
Anastasia Pimenova, BSc Hons
Leslie Shabani, BSc Hons
Adam Turner, BSc Hons (University of Ottawa)
Branka Vulesevic, DMV, MSc (University of Ottawa Heart Institute)
Kitty Wu, BSc Hons