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Dr. Lorrie Kirshenbaum

Dr. Lorrie Kirshenbaum

Director
Institute of Cardiovascular Sciences

Naranjan Dhalla Chair in Cardiovascular Sciences
Institute of Cardiovascular Sciences 

Principal Investigator
Cardiac Gene Biology, Institute of Cardiovascular Sciences

Professor
Department of Physiology & Pathophysiology, and Pharmacology & Therapeutics, University of Manitoba

Canada Research Chair
Molecular Cardiology, University of Manitoba

Director of Research Development
Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba

 

Discovering How to Turn Off a Gene

Dr. Lorrie Kirshenbaum’s laboratory is focused on understanding the molecular pathways and genetic factors that underlie the mechanisms of cardiac growth control and heart cell death. “There are certain genes that are highly regulated in the body that tell cells when to live and when to die, and we’re just beginning to understand why this takes place,” he explains. “We want to learn how these genes become turned on or turned off in disease processes.” Employing advanced techniques in molecular biology to this largely uncharted area of research, this laboratory is helping to set the stage for the use of gene therapy in the treatment of cardiovascular diseases.

Investigating Cell Suicide

The information encoded within DNA is responsible for programmed cell death or apoptosis, a process that has also been referred to as “cell suicide.” This mechanism is essential for removing unwanted or damaged cells from tissues. The process ensures that a delicate balance is maintained between the number of cells that are discarded and the number of cells that are formed. If the process is disrupted and too few cells die, it results in proliferative diseases such as cancer. If there is too much cell death, degenerative diseases such as Alzheimer’s will occur.

Because heart cells stop dividing at birth when they become damaged as a result of reduced blood flow due to atherosclerosis or other factors, they cannot repair themselves and the pumping activity of the heart is impaired. That is why it is so important to understand the genetic mechanisms that cause heart cells to die under different disease conditions.

Neonatal cells tend to be more resistant to cell death than adult cells because the genetic pathways that lead to the cell death process begin to change after birth. In comparing the two, the laboratory has identified two genes in particular that are linked to cell death. Using viruses to transfer the genes into individual heart cells, Dr. Kirshenbaum’s laboratory has been able to study their impact. One gene, a tumour suppressor protein that would normally be dormant, has been shown to become active and trigger apoptosis under certain disease conditions. Another gene has been discovered to have anti-apoptotic properties. Dr. Kirshenbaum has been able to demonstrate that these genes can be manipulated in rat heart cells to extend cell life and reduce the damage of heart disease.

Studying Cell Growth

Another component of Dr. Kirshenbaum’s studies is heart cell growth. After birth, when heart cells lose their ability to divide, they begin to increase in size to achieve growth of the organ. Also, a number of disease conditions, such as hypertension, cause the heart to enlarge in size. The laboratory is investigating whether the same stimuli that caused the heart cells to enlarge at birth become reactivated in a disease condition and whether those pathways can be manipulated genetically.

Cutting Edge Technology

Dr. Kirshenbaum’s approach is to understand heart disease at the genetic level. His lab was among the first to demonstrate the use of human viruses to deliver genes in the adult heart muscle cells. Using different viruses that are generated in the lab, the researchers insert the gene they wish to study into a virus, and the virus is able to “infect” the cell with the foreign DNA. The ultimate goal will be to correct the disease at the genetic level employing similar techniques.

For more information, please contact:

Lorrie Kirshenbaum, OM, PhD, FAHA, FIACS, FISHR, FFGTB, FCAHS

Naranjan Dhalla Chair in Cardiovascular Sciences,
Director, Institute of Cardiovascular Sciences
St. Boniface Hospital Albrechtsen Research Centre,
Canada Research Chair in Molecular Cardiology,
Head, Division of Cardiovascular Science and Disease,
Professor, Departments of Physiology and Pathophysiology, and
Pharmacology and Therapeutics, Max Rady College of Medicine
Rady Faculty of Health Sciences, University of Manitoba

Tel: (204) 235-3661
Fax: (204) 233-6723
lorrie@sbrc.ca

Amgalan D, Garner TP, Pekson P, Yanamandala M, Paulino V, Corbalan JJ, Lee J, Scarlata M, Liang H, Narayanagari SW, Mitchell K, Lopez A, Margulets V, Asnani A, Peterson R, Hazan RB, Steidl UG, Kirshenbaum LA, Gavathiotis E, and Kitsis RN. A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy. Nat Cancer 1, 315 – 328; 2020.

Rabinovich-Nikitin I, Rasouli M, Reitz CJ, Posen I, Margulets V, Dhingra R, Khatua TN, Thliveris JA, Martino TA, Kirshenbaum LA. Mitochondrial Autophagy and Cell Survival is Regulated by the Circadian Clock Gene in Cardiac Myocytes during Ischemic Stress. (11):3794-3812 Autophagy; Nov 2021 

Rabinovich-Nikitin I, Cogan R and Kirshenbaum LA. Attenuation of obesity cardiomyopathy by Ulk1/Rab9 mediated alternative mitophagy. Circ Res; 29(12): 1122-1124. Dec 2021 

Rabinovich-Nikitin I, and Kirshenbaum LA. Rev-erb-mediated Regulation of Cardiac Metabolism in the Obesity Paradox. Circulation. 145(6):465-468. Feb 2022. 

Zacharioudakis E, Agianian B, Kumar V, Biris N, Garner T, Rabinovich-Nikitin I, Ouchida AT, Margulets V, Nordstrom L, Riley J, Dolgalev I, Chen Y, Wittig A, Pekson R, Tsirigos A, Kirshenbaum LA, Kitsis R, Gavathiotis E. Modulating mitofusins to control mitochondrial function and signaling. Nat Commun. 13(1):3775. Jul 2022. 

Dhingra R, Rabinovich-Nikitin I, Rothman S, Guberman M, Gang H, Margulets V, Jassal DS, Alagarsamy KN, Dhingra S, Ripoll CV, Billia F, Diwan A, Javaheri A and Kirshenbaum LA. Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy. Circulation. 146(12):934-954. Sept 2022. 

Dhingra R and Kirshenbaum LA. Unc51-like-kinase 1-mediated mitophagy prevents pathological cardiac remodelling and heart failure. Cardiovasc Res.; 118(12):2561-2563. Sept 2022 

Rabinovich-Nikitin I and Kirshenbaum LA. Circadian regulated control of myocardial ischemia-reperfusion injury. Trends Cardiovasc Med. S1050-1738(22)00120-7. 2022.

 

Order of Manitoba, Government of Manitoba (2023 )

University of Kragujevac, Faculty of Medical Sciences, Visiting Professorship (Kragujevac, Serbia) (2023)

 Lifetime Achievement Award – International Academy of Cardiovascular Sciences (Winnipeg, Canada) (2022)

Naranjan Dhalla Honorary Lectureship Award, International Academy of Cardiovascular Sciences (Banja Luka, Bosnia and Herzegovina) ( 2021)

Suresh K. Gupta Oration Lectureship Award, International Conference of Cardiovascular Sciences, New Delhi, India (2020)

Canadian Cardiovascular Society, Research Achievement Award, Ottawa, Canada (2020)

James T. Willerson Distinguished Lectureship Texas Heart Institute, Houston, USA (2019)

Bohuslav Ostadal Award for Excellence in Cardiovascular Sciences, International Academy of Cardiovascular Sciences, Belgrade, Serbia (2019)

Canada Research Chair Tier I in Molecular Cardiology (2018)

Fellow of the International Society for Heart Research (2010)

Fellow of American Heart Association (2009)

University of Manitoba Merit Award for Research, Faculty of Medicine University of Manitoba (2009)

Distinguished Chemist Award, Chemical Institute of Canada (2008)

Canada Research Chair Tier II in Molecular Cardiology (2005-present)

Dr. R.E. Beamish Memorial Award for Top-Ranked Grant Awarded by the Heart and Stroke Foundation of Manitoba (2003-2004)

Canada Research Chair Tier II in Molecular Cardiology (2001-2005)

Rh Institute Foundation Award for Excellence in Health Research – Clinical (2003)

Ken Hughes Young Investigator Award for Medical Research (2002)

Canadian Cardiovascular Society – Robert E. Beamish Award (2000)

Canadian Society for Clinical Investigation – Joe Doupe Young Investigator Award (2000)

We gratefully acknowledge support from the following funding agencies:

Current Funding and External Grant Support:

  • Canadian Research Chair Programs
  • Canadian Institutes of Health Research Operating Grants
  • St. Boniface Hospital Foundation
Dr. Kirshenbaum’s laboratory invites applications for Graduate Students and Post-Doctoral Fellows. Please forward an application and academic CV to Dr. Lorrie Kirshenbaum at lorrie@sbrc.ca .

Life In the Lab