Regulation of neuronal gene expression by secretory leukocyte protease inhibitor

分泌性白细胞蛋白酶抑制剂对神经元基因表达的调节

• 批准号: RGPIN-2016-05977
• 负责人: Hannila, Sari
• 金额: $ 2.26万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684040
• 关键词: Regulation; neuronal; gene; expression; secretory

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.

基因可以说是细胞最重要的组成部分，因为它们负责产生对细胞的生存和功能至关重要的蛋白质。当基因发生突变时，可能会产生有毒或功能失常的蛋白质，这可能会导致功能障碍，甚至细胞死亡。基因突变对神经系统的影响可能特别严重，因为如果神经元受损或被摧毁，神经元就不会被替换，这可能会导致运动功能和记忆的永久性缺陷。因此，重要的是要了解神经元中基因表达是如何调节的，并找到中和突变基因影响的方法。这项研究计划将研究一种名为分泌性白细胞蛋白酶抑制物(SLPI)的蛋白质如何阻止突变基因的表达。SLPI是一种常见于唾液中的小蛋白，它以其消炎和杀灭细菌的能力而闻名。最近，人们发现SLPI可以与DNA中称为启动子的区域结合，并阻止特定基因的表达。我的实验室最近完成了一项大规模研究，使用最先进的技术识别了2000多个受SLPI调控的基因，我们已经分析了这些数据，以识别在神经系统中发挥重要作用的基因。我的NSERC Discovery研究项目的目标将是研究SLPI如何调节神经系统中的基因表达，以及SLPI的丢失如何影响大脑功能。在我们的第一系列实验中，我的团队将验证我们已经确定的目标基因，以确认SLPI可以调节它们的表达，这将使用基因报告分析来完成。我们的下一个目标将是确定SLPI的丢失是否会导致携带与神经退化相关的突变的小鼠神经元死亡增加，我们还将测试SLPI的治疗是否可以逆转这一效应并促进细胞存活。最后，我们将通过检测SLPI调节突触功能相关基因表达的能力来研究SLPI在正常神经系统功能中的作用。突触是神经元之间的连接，允许它们相互通信。我们将测试缺乏SLPI的小鼠是否在学习和记忆任务的能力方面表现出缺陷，我们还将检查这些小鼠的大脑，以寻找突触没有正确形成的迹象。这些研究将是世界上第一次进行此类研究，因此，将在该项目中接受培训的研究生将有无与伦比的机会进行尖端神经科学研究。最重要的是，这项工作将使我们能够更深入地了解管理学习、记忆和神经退化的基本过程，我们将能够利用这些信息制定旨在防止大脑退化的新策略--随着加拿大人口老龄化，大脑退化正变得至关重要。