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: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629914
• 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生存和功能至关重要的蛋白质。当基因发生突变时，会产生有毒或功能失调的蛋白质，这可能导致功能失调甚至细胞死亡。基因突变对神经系统的影响尤其严重，因为如果神经元受损或被破坏，它们就无法被替换，这可能导致运动功能和记忆的永久性缺陷。因此，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是很重要的。这个研究项目将研究一种叫做分泌性白细胞蛋白酶抑制剂（SLPI）的蛋白质如何阻止突变基因的表达。SLPI是唾液中常见的一种小蛋白质，以其减少炎症和杀死细菌的能力而闻名。最近，人们发现SLPI可以与称为启动子的DNA区域结合，并阻断特定基因的表达。我的实验室最近完成了一项大规模的研究，使用最先进的技术来识别超过2000个由SLPI调节的基因，我们分析了这些数据来识别在神经系统中起重要作用的基因。我的NSERC发现研究计划的目标是研究SLPI如何调节神经系统中基因的表达，以及SLPI的缺失如何影响大脑的功能。在我们的第一个系列实验中，我的团队将验证我们已经确定的靶基因，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。我们的下一个目标是确定SLPI的缺失是否会导致携带与神经变性相关突变的小鼠神经元死亡增加，我们还将测试SLPI治疗是否可以逆转这种影响并促进细胞存活。最后，我们将研究SLPI在正常神经系统功能中的作用，通过检查其调节参与突触功能的基因表达的能力——突触是神经元之间的连接，使它们能够相互交流。我们将测试缺乏SLPI的小鼠是否在学习和记忆任务方面表现出缺陷，我们还将检查这些小鼠的大脑，寻找突触未正确形成的迹象。这些研究将是世界上同类研究的首例，因此，在这个项目中接受培训的研究生将有无与伦比的机会进行前沿神经科学研究。最重要的是，这项工作将使我们对控制学习、记忆和神经退化的基本过程有更深入的了解，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，这一领域变得至关重要。