Department of Physiology, University of Manitoba
Canada Research Chair
Molecular Cardiology, University of Manitoba
Director of Research Development
Faculty of Medicine, University of Manitoba
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.
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 tumor 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.
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.
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:
Dr. Lorrie Kirshenbaum
Shaw J, Yurkova N, Zhang T, Gang H, Aguilar F, Weidman D, Scramstad C, Weisman H and Kirshenbaum LA. Antagonism of E2F-1 regulated Bnip3 transcription by NF-κB is essential for basal cell survival.
Proc Natl Acad Sci 105(52); 20734-20739:2008.
Li GH, Shi Y, Chen Y, Sun M, Sader S, Maekawa Y, Arab S, Dawood F, Chen M, De Couto G, Liu Y, Fukuoka M, Yang S, Da Shi M, Kirshenbaum LA, Gelsolin Regulates Cardiac Remodeling After Myocardial Infarction Through DNase I–Mediated Apoptosis. McCulloch CA, Liu P. Circ Res. 104(7):896-904; 2009.
Gang H, Aviv Y, Hai Y, Dhingra R, Aguilar F, Yurkova N, Gordon JW, Leygue E and Kirshenbaum LA. A Novel Hypoxia-Inducible Splice Variant of Death Gene Gnip3 Promotes Survival of Ventricular Myocytes. Circ Res. 108(9): 1084-1092; 2011.
Gordon JW, Shaw J and Kirshenbaum LA. Multiple Facets of NF-kB in the Heart: to Be or Not to NF-kB. Circ Res. 108(9):1122-1132; 2011
Panama BK, Latour-villamil D, Farman GP, Zhao D, Bolz SS, Kirshenbaum LA and Backx PH. NF-kB Down regulates the transient Outward Potassium Current Ito, f Through Control of KChIP2 Expressions. Circ Res. 108(5):537-43; 2011
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)
The ripple effect
The Suicide Gene
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 firstname.lastname@example.org .