Ormiston, PhD | Department of Surgery | School of Medicine

Mark Ormiston, PhD

Position(s)

Associate Professor

Contact Info

T. 613.533.6241

Research Interests:

My research is centered on the cellular mechanisms governing vascular remodeling in health and disease, with a particular focus on the capacity of circulating cells of the immune system to regulate blood vessel integrity, growth and repair. This interest is rooted in my study of pulmonary arterial hypertension (PAH), a disease of pathological vascular remodeling and right heart failure that is linked to immune dysfunction. PAH is strongly associated with loss-of-function mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR-II), a receptor of the transforming growth factor-β (TGFβ) superfamily. Identification of this link between PAH and BMPR-II haploinsufficiency has provided considerable insight into the mechanisms governing pulmonary vascular homeostasis and makes PAH an ideal candidate for proof-of-concept regenerative and cell-based therapeutic strategies.

More specifically, I am interested in the capacity of innate lymphocytes, such as Natural Killer (NK) cells, to influence vascular growth and repair. Beyond their traditional role as the cytotoxic effector cells of innate immunity, there is a growing body of literature supporting a role for NK cells in the regulation of vascular remodelling, particularly in pregnancy. My previous work has identified a phenotypic and functional defect in the circulating NK cells of PAH patients, associated with increased TGFβ signalling and elevated production of matrix metalloproteinase (MMP)-9 by these cells. Through my ongoing studies, I aim to (i) determine the mechanisms by which NK cells influence pulmonary vascular homeostasis in health and disease and (ii) clarify the impact of BMPR-II mutations on these processes.

EMPLOYMENT AND EDUCATION

Assistant Professor

October 2015 - 2020

Queen’s University, Kingston, ON Canada

Funding: Tier II Canada Research Chair, Canadian Institutes of Health Research

CURRENT FUNDING

Tier II Canada Research Chair in Regenerative Cardiovascular Medicine, Canadian Institutes of Health Research. 2015-2020. $500,000.

Project Grant, Canadian Institutes of Health Research. “Cellular and molecular mechanisms of Natural Killer cell-mediated vascular remodeling in pulmonary arterial hypertension.”

2017-2022. $830,025. Role: Principal Investigator.

2016-2017. $100,000 bridge grant. Role: Principal Investigator.

William M. Spear Endowment Fund in Pulmonary Research/ Richard K. Start Memorial Fund, Queen’s University Faculty of Health Sciences. “Immunophenotyping of natural killer cells from pulmonary arterial hypertension patients using CyTOF mass cytometry.”

2017-2018. $25,500

Role: Principal Investigator

John Alexander Stewart Postdoctoral Fellowship (Salary award for Dr. M. Ratsep), Queen’s University Department of Medicine. “Interleukin-15 signalling by the pulmonary endothelium, and its role in regulating Natural Killer cell homeostasis and pathogenesis of pulmonary arterial hypertension.”

2017-2018 $40,000

Role: Supervisor

Seed Grant – Research Team Project, Canadian Vascular Network. “A central role for hsa-miR-138-5p and the Mitochondrial Calcium Uniporter (MCU) in human and experimental PAH.”

2016-2018 $100,000

Role: Co-investigator (PI: Dr. Stephen Archer)

Research Leader’s Fund, Queen’s University. “Generation of blood outgrowth endothelial cells for the study of immune dysfunction in pulmonary arterial hypertension.”

2016-2018 $50,000

Role: Principal Investigator

John R. Evans Leaders Fund, Canadian Foundation for Innovation.

2015-2016 $175,000

Small Infrastructure Fund, “Regenerative Cardiovascular Medicine Laboratory.” Ontario Research Fund.

2015-2016 $175,000

Role: Principal Investigator

PENDING FUNDING

Project Grant, Canadian Institutes of Health Research. “Understanding the Role of von Willebrand Factor in Angiodysplasia.”

2018-2021 $450,000

Role: Collaborator. (PI: Dr. Paula James)

PREVIOUSLY HELD GRANTS AND AWARDS

National Grant Review/Grant-In-Aid, Ontario Thoracic Society. “Examining the impact of endothelial BMPR2 loss on immune dysfunction in the pathogenesis of pulmonary arterial hypertension.”

2016-2017 $50,000

Role: Principal Investigator

William M. Spear Endowment Fund in Pulmonary Research/ Richard K. Start Memorial Fund, Queen’s University Faculty of Health Sciences. “Interleukin-15 signaling and pulmonary hypertension in mice bearing an endothelial-specific deletion of bmpr2.”

2016-2017 $25,000

Role: Principal Investigator

Summer Work Exchange Program (SWEP) Studentship, Queen’s University.

2017 $6,527

Role: Supervisor - conceived project and wrote proposal

Summer Work Exchange Program (SWEP) Studentship, Ms. Anne Theilmann, Queen’s University.

2016 $6,527

Supervisor: Conceived project and wrote proposal

PUBLICATIONS

PEER-REVIEWED ORIGINAL RESEARCH

Under review/In revision

M. Rätsep, S.D. Moore, S. Jafri, H.J.M. Brady, O. Mandelboim, M. Southwood, N.W. Morrell, F. Colucci, M.L. Ormiston. “Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency.” Submitted to The American Journal of Physiology, Lung Cellular and Molecular Physiology, September 2017. Reviewed and in revision.

B. Garfield, A. Crosby, D. Shao, P. Yang, R. Paul, S. Sawiak, M.L. Ormiston, S. Moore, L. Parfitt, C. Harries, N.W. Morrell, M. Polkey, S. J. Wort, P. Kemp. “Growth and differentiation factor 15 mediated skeletal muscle loss in pulmonary arterial hypertension is transforming growth factor activated kinase 1 dependent.” Submitted to Thorax, December 2017.

K.H. Chen, A. Dasgupta, J. Lin, F. Potus, S. Bonnet, J. Iremonger, J. Fu, J. Mewburn, D. Wu, K. Dunham-Snary, Z. C. Jing, Anne L. Theilmann, C. Hindmarch, M.L. Ormiston, A. Lawrie, S.L. Archer “Critical role of MiD49 and MiD51 mediated mitotic fission in human vascular disease.” Submitted to Circulation, August 2017. Reviewed and resubmitted.

E. Ferrer, B.J. Dunmore, M.L. Ormiston, S. Moore, J. Deighton, L. Long, X.D. Yang, D.J. Stewart, N.W. Morrell. “Translationally controlled tumor protein export via exosomes is involved in vascular remodeling in pulmonary arterial hypertension.” Submitted to The American Journal of Respiratory Cell and Molecular Biology, July, 2017. Reviewed and resubmitted.

Published/In press

P. Caruso, B.J. Dunmore, K. Schlosser, S. Schoors, C. Dos Santos, C. Perez-Iratxeta, J. Lavoie, L.L. Long, L. Hurst, M.L. Ormiston, A. Hata, P. Carmeliet, D.J. Stewart, N.W. Morrell. “Identification of miR-124a as a major regulator of enhanced endothelial cell glycolysis in pulmonary arterial hypertension by miRNA and proteomic profiling.” Circulation. 2017 Sep 26. [Epub ahead of print].

S. Jafri, S.D. Moore, N.W. Morrell, M.L. Ormiston. “A sex-specific reconstitution bias in the competitive CD45.1/CD45.2 congenic bone marrow transplant model.” Scientific Reports. 2017 Jun 14;7(1):3495.

S.N. Selvam, L.J. Casey, M.L. Bowman, L.G. Hawke, A.J. Longmore, J. Mewburn, M.L. Ormiston, S.L. Archer, D.H. Maurice, P. James. “Abnormal angiogenesis in blood outgrowth endothelial cells derived from von Willebrand disease patients.” Blood Coagulation and Fibrinolysis. 2017 March 30. [Epub ahead of print]

Z. Hong, K.H. Chen, A. DasGupta, F. Potus, K. Dunham-Snary, S. Bonnet, L. Tian, J. Fu, S. Breuils-Bonnet, S. Provencher, D. Wu, J. Mewburn, M.L. Ormiston, S.L. Archer. “miR-138 and miR-25 Downregulate MCU, Causing Pulmonary Arterial Hypertension’s Cancer Phenotype.” The American Journal of Respiratory and Critical Care Medicine. 2017 Feb 15;195(4):515-529

BOOK CHAPTERS AND REVIEWS

Published/In press

T. Thenappan, M.L. Ormiston, J. Ryan, S.L. Archer. “Etiology, Diagnosis and Management of Pulmonary Arterial Hypertension.” Invited review, The British Medical Journal. In press.

S. Jafri and M.L. Ormiston. “Immune regulation of systemic hypertension, pulmonary arterial hypertension and preeclampsia: shared disease mechanisms and translational opportunities.” The American Journal of Physiology, Regulatory, Integrative and Comparative Physiology. 2017 Oct 4 [Epub ahead of print]

PUBLISHED AND OTHER SELECTED ABSTRACTS

A.L. Theilmann, L. Hawke, R.L. Hilton, J. Mackeil, K.J. Dunham-Snary, P.D. James, D.H. Maurice, S.L. Archer, M.L. Ormiston “Sub-haploinsufficiency of BMPR2 causes a shift in the endothelialproliferative and metabolic response to BMP9.” Submitted to the American Thoracic Society International Conference, San Diego, CA. May 2018.

INVITED ORAL PRESENTATIONS

“Innate Lymphoid Cell plasticity in chronic hypoxia and pulmonary vascular disease” 10th Annual Luis G. Melo Memorial Lecture. Queen’s University. November 29, 2017.

“Natural Killer cells in pulmonary vascular disease.” Beckman Coulter CytoFLEX LX tour. University of Ottawa. June 15, 2017.

“Historical perspective on stem cells in PAH.” Pulmonary Vascular Research Institute Annual World Congress. Miami, FL. January 26, 2017.

“Stem Cell Therapies for Cardiovascular Disease: Facts & Fiction.” Queen’s University Department of Medicine 3rd Annual Continuing Medical Education Day. Kingston, Ontario, Canada. May 11, 2016.

“Targeting Endothelial and Immune Dysfunction for the Treatment of Pulmonary Vascular Disease.” Queen’s University Department of Biomedical and Molecular Sciences Plenary Lecture Series. Queen’s University, Kingston, Ontario, Canada. May 3, 2016.

“Examination of cardiopulmonary function in mouse models of Natural Killer cell deficiency.” Stanford University 2nd International Symposium on Immunity and the Pathogenesis of Pulmonary Hypertension. Stanford, CA. November 6, 2015.

Team

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