Dr. Lorrie Kirshenbaum’s expertise extends to the design, construction and implementation of recombinant adenovirus vectors, to genetically modify adult and neonatal cardiac muscle cells from normal and diseased hearts. Dr. Kirshenbaum’s research is directed toward understanding the molecular mechanisms and signaling factors that govern cardiac gene expression during early cardiac cell growth as well as cell death (apoptosis) during the pathogenesis of heart failure. Moreover, his research focus include cellular factors that regulate cell cycle control and cardiac regeneration in genetically engineered mouse models. Dr. Kirshenbaum’s research program is highly regarded and funded by multiple grants by the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Canada. Dr. Kirshenbaum was recently awarded a prestigious Canada Research Chair in Molecular Cardiology.
Shortly after birth, cardiac muscle cells lose their ability to divide. This inherent property of the heart results in the subsequent growth of the neonatal myocardium occurring by an increase in cell size (cardiac hypertrophy) rather than by cell number (hyperplasia). This basic and fundamental property of cardiac tissue has profound implications for individuals who develop heart disease, since once the heart cells are damaged, they are not replaced with new cells, which significantly impacts on cardiac function resulting in eventual heart failure.
Toward this goal, Dr. Kirshenbaum has identified that specific genes within the heart, particularly the tumor suppressor protein p53 is up-regulated during disease states and provokes a genetically regulated form of cell death referred to as apoptosis. Importantly, Dr. Kirshenbaum’s research has further identified that human factor Bcl-2, initially identified in B-cell lymphomas has anti-apoptotic properties and can suppress cardiac cell death when delivered to heart via a recombinant adenovirus. These highly significant and novel findings demonstrate for the first time that cardiac cells can be genetically modified to be more resistant to death promoting signals. These seminal and important observations have very broad and far reaching implications that when applied extend beyond our basic understanding of heart disease to other disease entities such as cancer. Dr. Kirshenbaum is currently investigating the cellular targets of the Bcl-2 protein in cells, and its impact on the cellular targets that dually regulate cell growth and cell death process during hypoxia and myocardial infarction. In this regard, Dr. Kirshenbaum has identified that Bcl-2 proteins when expressed in cells activates the transcription factor NF-kB, recently implicated as a key regulator of the apoptotic process.
Other investigations by Dr. Kirshenbaum include the study of a class of cellular cysteine proteases known as caspases and role in mediating mitochondrial defects and apoptosis of cardiac muscle cells during hypoxia. In this regard, Dr. Kirshenbaum’s laboratory has identified that caspase 8 becomes proteolytically activated in ventricular myocytes during hypoxia. Furthermore, hypoxia-induced activation of caspase 8 resulted in mitochondrial defects consistent with the loss of mitochondrial membrane potential, permeability transition pore opening and loss of cytochrome c by mitochondria. Dr. Kirshenbaum verified the operation of caspase-dependent mitochondrial regulated pathway for the induction of apoptosis of cardiac myocytes during hypoxia by demonstrating that the cow pox virus modifier A gene (CrmA) which has an inherent affinity to block the activation of caspase 8, suppressed hypoxia-mediated mitochondrial defects and apoptosis of ventricular myocytes. These important studies established for the first time the involvement of caspase 8 and mitochondria dependent pathway for hypoxia-induced apoptosis of cardiac myocytes. In addition, Dr. Kirshenbaum has recently cloned a novel mitochondrial death factor known as BNIP3 for (Bcl-2 Nineteen Kildaton Interacting Protein) a member of the BH3 only domain family members of the Bcl-2 gene family. Dr. Kirshenbaum has identified that BNIP3 is selectively and completely induced in ventricular myocytes during hypoxia. Moreover, BNIP3 was found to integrate into mitochondrial membranes and provoke mitochondrial perturbations consistent with the loss of mitochondrial membrane potential, permeability transition pore opening, release of Smac/Diablo, cytochrome c release and caspase activation. The carboxyl-terminal transmembrane domain was identified to be important for BNIP3 induced killing, since mutations of this region rendered BNIP3 defective for mitochondrial integration and abrogated its ability to provoke cell death. These important studies highlight BNIP3 as key regulatory factor that is crucial for trigger mitochondrial perturbations and cell death of ventricular myocytes. Future studies are directed toward elucidating the signaling pathways and cellular targets involved with BNIP3 induced cell death as well as the role of BNIP3 during heart failure in genetically altered mice.
Research Publications: PubMed