Grant: Discovery Development Grant

My lab studies apoptosis, a type of programmed cell death. It is regulated by specific genes, in response to different stimuli. As a consequence, apoptosis is a highly regulated event. One aspect of this regulation occurs when genes are expressed, by a process called alternative splicing. Some proteins that regulate apoptosis, such as CASPASE 2, are alternatively splicing to produce both pro- and anti-apoptosis proteins. In addition, the proteins responsible for the regulation of these key apoptosis regulatory factors can also experience alternative splicing, with consequences for apoptosis regulation. For instance, RBM5 is a protein with the ability to regulate CASPASE 2 alternative splicing, but the transcript encoding RBM5 protein is itself alternatively spliced, with functional consequences for apoptosis regulation. In my lab, we are particularly interested in the role played by RBM5, and a related protein RBM10, in modulating both alternative splicing and apoptosis. My research program is aimed at understanding how RBM5 and RBM10 function to regulate apoptosis. This involves (a) gaining a better understanding of the targets of RBM5 and RBM10, and the RBM5 and RBM10 mechanisms of action, and (b) identifying the regulators of RBM5 and RBM10 expression and function. Over the years we have demonstrated that both RBM5 and RBM10 are able to influence cell death by regulating the expression of a subset of cellular factors. This work in ongoing. We have recently begun to investigate what regulates the expression of both RBM5 and RBM10. My short-term objective is to focus on target identification for RBM5, RBM10 and the structural variants thereof. We are carrying out our investigations using two model systems. One is a muscle model and the other is a lung model. The muscle model represents a normal developmental process that involves preventing cell multiplication and promoting death in a subset of cells. The lung model represents a cancer system, where apoptosis is always disrupted at some level, and both RBM5 and RBM10 are known to be downregulated. Using these two models we hope to shed light on how RBM5 and RBM10 function in normal cells and what regulates this function.  The anticipated impact of our study is that the results will provide the first physiologically relevant information regarding RBM5 and RBM10 target interactions, insight into how the expression of RBM5 and RBM10 are regulated, and information concerning whether or not their regulation is related. With this work, we hope to gain a better understanding of apoptosis regulation, and in particular, the role played by alternative splicing in this regulation.