Regulation of neuronal gene expression by secretory leukocyte protease inhibitor

点击翻译按钮获取中文摘要

Genes are arguably the most important components of a cell, as they are responsible for producing the proteins that are vital to a cell's survival and function. When genes are mutated, toxic or malfunctioning proteins can be produced, and this can lead to dysfunction or even cell death. The effects of gene mutations can be particularly devastating in the nervous system because neurons are not replaced if they are damaged or destroyed, and this can lead to permanent deficits in motor function and memory. It is therefore important to understand how gene expression is regulated in neurons, and to find ways of neutralizing the effects of mutated genes. This research program will examine how a protein called secretory leukocyte protease inhibitor (SLPI) can block the expression of mutated genes. SLPI is a small protein commonly found in saliva, and it is best known for its ability to reduce inflammation and kill bacteria. More recently, it was discovered that SLPI can bind to regions of DNA called promoters and block the expression of specific genes. My laboratory has recently completed a large-scale study that used state-of-the-art techniques to identify over 2000 genes that are regulated by SLPI, and we have analyzed this data to identify genes that play important roles in the nervous system. The goal of my NSERC Discovery research program will be to investigate how SLPI regulates the expression of genes in the nervous system, and how loss of SLPI can affect the function of the brain. In our first series of experiments my group will validate the target genes that we have identified to confirm that SLPI can regulate their expression, and this will be done using gene reporter assays. Our next goal will be to determine if loss of SLPI leads to increased neuron death in mice that carry mutations that are associated with neurodegeneration, and we will also test if treatment with SLPI can reverse this effect and promote cell survival. Finally, we will investigate SLPI's role in normal nervous system function by examining its ability to regulate the expression of genes that are involved in the function of synapses - the connections between neurons that allow them to communicate with one another. We will test whether mice lacking SLPI display deficits in their ability to learn and remember tasks, and we will also examine the brains of these mice for signs that synapses have not formed correctly. These studies will be the first of their kind in the world, and so, the graduate students who will be trained in this program will have unparalleled opportunities to conduct cutting-edge neuroscience research. Most importantly, this work will allow us obtain greater insight into the fundamental processes that govern learning, memory, and neurodegeneration, and we will be able to use this information to develop new strategies aimed at preventing degeneration of the brain - an area that is becoming critically important as Canada's population ages.