A translational research lab at Temple University.
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Heart failure and myocardial infarction, as well as many other diseases, are characterized by significant metabolic dysfunction and cell death both of which have been shown to initiate and drive disease. Mitochondrial calcium signaling is central to these processes regulating both oxidative phosphorylation (energy production) and cell death. While much is known about how calcium exchange is regulated at the plasma membrane and ER/SR our understanding of the mitochondrial calcium microdomain remains elementary. The lab utilizes in vitro and in vivo techniques ranging from real-time measurements of calcium exchange in isolated cells to surgical and genetic animal models of disease to decipher the role of this cellular microdomain in the progression of heart failure and myocardial infarction.
NECROTIC CELL DEATH
Historically, necrotic cell death (characterized by cell swelling, membrane rupture, lysis and inflammation) has largely been thought to be a non-specific/unprogrammed process and thereby void of distinct signaling events and genetic players. Recently, it has become clear that necrosis, like apoptosis, may be highly regulated and involve specific gene programs. Of clinical importance, cellular necrosis underlies many human disease states such as ischemic injury, neurodegenerative diseases, and other adult onset diseases. The lab has various projects examining genes and pathways that contribute to cellular necrosis with the hope of finding new therapeutic targets to block cell death in disease.
Heart failure is characterized by a decrease in contractility and maladaptive remodeling ultimately leading to impaired cardiac output to the systemic circulation. The incidence of heart failure in the US is predicted to increase dramatically over the next 20 years. It is estimated that over 8 million people in the US will be diagnosed with HF by the year 2030 (1 in every 33 individuals) and total costs associated with the disease are projected to climb to $160 billion, representing a substantial health and economic burden on the US. Numerous studies in the lab are trying to understand how this disease develops and searching for new treatments. Facilitating these studies, the lab utilizes various mouse models of heart failure including myocardial infarction, transaortic constriction (pressure-overload) and various mutant genetic models.
Ischemia-Reperfusion (IR) injury is incurred when when blood flow to a tissue is blocked and then restored. This is a multifaceted process with significant tissue damage resulting from the lack of oxygen and nutrients and also the oxidative burst that occurs with the rapid restoration of blood flow. The most well characterized types of IR injury are myocardial infarction (coronary blockage) and stroke (blocking blood flow to regions of the brain). One of our primary areas of investigation is to uncover new mechanisms for how this type of injury progresses and discover new therapies to aid cell survival and preserve cardiac function in the setting of a heart attack.
MOUSE MODELS OF DISEASE
The lab regularly uses and generates new mutant mouse models for conditional overexpression or ablation of a given gene . These models allow causative testing to see if a gene really does alter the progression of disease in the intact animal. These studies are made possible by an outstanding transgenic core facility at Temple Fox Chase Cancer Center. The use of animal models allows us to assess the translational potential of a given therapy and is central to examining the likelihood of how a therapy may impact human disease.
This project first began at Cincinnati Children's Hospital in the lab of Dr. Jeff Molkentin where Dr. Elrod established a high-throughput screening core. The goal of this project is to discover modulators of programmed necrosis with the hopes of finding new genetic targets to block cell death. The lab utilizes non-biased, genome-wide functional screening in cell-based assay systems. To aid in this discovery project different types of tools are utilized including shRNA lentiviral, cDNA, and small molecule libraries. Coupling these screening techniques with bioinformatics/systems biology analyses we have identified unique players and pathways in programmed necrosis and are investigating their mechanisms of action.