Contact Information

Manon Levesque Departmental Secretary of Pathology and Laboratory Medicine
451 Smyth road,
Room 4155
Ottawa, Ontario
K1H 8M5

Telephone: 613-562-5422
Fax: 613-562-5442
Email: mlevesq2@uottawa.ca

Sheila Schnupp
Office and Residency Program Administrator (Anatomical)
Telephone: 613-562-5800 ext. 8342
Fax: 613-562-5442
Email: sschnupp@uottawa.ca

John P. Veinot, M.D., F.R.C.P.C (Canada)
Chairman, Department of Pathology and Laboratory Medicine
Tel: 613-562-5422
Fax: 613-562-5442
Email: sschnupp@uottawa.ca

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Thomas Lagacé

Thomas Lagacé

B.Sc. (University of New Brunswick), PhD (Dalhousie University, Halifax)

Assistant Professor
Department of Pathology and Laboratory Medicine
Faculty of Medicine.

Lipoprotein Receptor Biology Laboratory
University of Ottawa Heart Institute
Ottawa, Ontario

Telephone: 613-761-4741
Fax: 613-761-5821
Email: tlagace@ottawaheart.ca

Areas of Laboratory Medicine Expertise

  • Lipid and Protein Biochemistry
  • Cell Biology
  • Molecular Biology
  • Lipid Metabolism

Research Interests

Dr. Lagace is a Cardiovascular Research Scientist who directs the Lipoprotein Receptor Biology Laboratory at the University of Ottawa Heart Institute.  The research in the laboratory of Dr. Lagace is focused on mechanisms that regulate circulating plasma cholesterol levels and associated heart disease risk.

Cholesterol metabolism: The removal of cholesterol packaged in low-density lipoprotein (LDL) from the circulation occurs mainly in liver via the LDL receptor, a cell surface glycoprotein that binds to LDL particles with high affinity and mediates their uptake into cells. This process is subject to regulatory mechanisms that maintain tight control of cellular cholesterol levels.  We are studying cellular and circulating factors that affect cell surface LDL receptor levels utilizing cell culture and mouse models as well as protein-protein interaction studies with purified protein components.

Intracellular cholesterol trafficking and signaling:  The ability of cells to internalize and degrade LDL via the LDL receptor pathway is subject to a negative feedback mechanism that is sensitive to levels of cholesterol in cell membranes.  The cholesterol content in the endoplasmic reticulum (ER) organelle of the cell plays a dominant role in this process. The movement to the ER of LDL-derived free cholesterol from the site of LDL degradation in lysosomes is an important component of negative feedback control that remains poorly understood.  We are studying the role of membrane phospholipids and ER-localized cholesterol storage mechanisms in regulating the lysosome-to-ER cholesterol trafficking pathway and cellular responses to LDL-derived cholesterol.

Publications

  • Susan G. Lakoski, Thomas A. Lagace, Jonathan C. Cohen, Jay D. Horton, and Helen H. Hobbs (2009) Plasma levels of PCSK9 in a large multiethnic population. Journal of Clinical Endocrinology and Metabolism 94(7), pp. 2537-2543.
  • Thomas A. Lagace (2009) PCSK9 and heart disease: quieting an outdated metabolic moderator. Clinical Lipidology  4(4), pp. 407-410.
  • Markey C. McNutt, Hyock Joo Kwon, Chiyuan Chen, Justin R. Chen, Jay D. Horton and Thomas A. Lagace (2009) Antagonism of Secreted PCSK9 Increases Low-Density Lipoprotein Receptor Expression in HepG2 Cells. Journal of Biological Chemistry 284, pp. 10561-10570.
  • Karsten Gehrig, Thomas A. Lagace and Neale D. Ridgway (2009) Oxysterol activation of phosphatidylcholine synthesis involves CTP:phosphocholine cytidylyltransferase alpha translocation to the nuclear envelope. Biochemical Journal 418(1) pp.209-217.
  • Aldo Grefhorst, Markey C. McNutt, Thomas A. Lagace, and Jay D. Horton (2008) Plasma PCSK9 Functions to Preferentially Reduce Liver LDL Receptors in Mice. Journal of Lipid Research 49, pp. 1303-1311.
  • Hyock Joo Kwon, Thomas A. Lagace, Markey C. McNutt, Jay D. Horton, and Johann Deisenhofer (2008)  Molecular basis for LDL receptor recognition by PCSK9.  Proceedings of the National Academy of Sciences 105, pp.1820-1825.
  • Markey C. McNutt, Thomas A. Lagace, and Jay D. Horton (2007) Catalytic Activity is Not Required for Secreted PCSK9 to Reduce LDL Receptors in HepG2 Cells. Journal of Biological Chemistry 282, pp. 20799-20803.
  • Da-Wei Zhang, Thomas A. Lagace, Rita Garuti, Zhenze Zhao, Meghan McDonald, Jay D. Horton, Jonathan C. Cohen and Helen H. Hobbs (2007) Binding of Proprotein Convertase Subtilisin/Kexin Type 9 to Epidermal Growth Factor-like Repeat A of Low Density Lipoprotein Receptor Decreases Receptor Recycling and Increases Degradation. Journal of Biological Chemistry 282, pp. 18602-18612.
  • Thomas A. Lagace, David E. Curtis, Rita Garuti, Markey C. McNutt, Sahng Wook Park, Heidi B. Prather, Norma N. Anderson, Y. K. Ho, Robert E. Hammer, and Jay D. Horton (2006) Secreted PCSK9 Decreases LDL Receptors in Hepatocytes and in Livers of Parabiotic Mice. Journal of Clinical Investigation 116(11) pp. 2995-3005.
  • Zhenze Zhao, Yetsa Tuakli-Wosornu, Thomas A. Lagace, Lisa Kinch, Nicholas V. Grishin, Jay D. Horton, Jonathan C. Cohen, and Helen H. Hobbs (2006) Molecular Characterization of Loss-of-Function Mutations in PCSK9 and Identification of a Compound Heterozygote.  American Journal of Human Genetics 73(9) pp. 514-523.

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