Transcriptional mechanisms of neural stem cell maintenance and neurogenesis

这个项目的目的是更好地了解干细胞是如何决定是增殖还是生成神经细胞。干细胞是至关重要的祖细胞，它能产生形成胚胎器官的所有特化细胞。它们也存在于成人器官中，在那里它们需要维持和修复。每个器官都有自己的干细胞，可以产生该器官的特定细胞类型。在医学上，干细胞可以用来取代疾病中受损的细胞；例如，血液干细胞被用来治疗白血病。为了将干细胞的用途扩展到其他疾病的治疗，我们必须更多地了解干细胞是如何工作的。特别是，我们需要更好地理解干细胞变得专门化以产生一种细胞而不是另一种细胞的过程。在这个项目中，我们将研究神经系统的干细胞(称为神经干细胞)如何成为专门生成神经细胞(神经元)的细胞。这一过程涉及一组活跃基因的深刻变化：干细胞中存在的基因被关闭，而神经元特有的基因变得活跃。基因活性由称为转录因子的蛋白质控制。控制我们大脑神经元生成的主要转录因子之一被称为Ascl1。这个项目的主要目的是了解Ascl1如何改变神经干细胞中的活性基因集，使这些细胞产生新的神经元。转录因子通过与它们激活的基因附近的DNA结合来发挥作用。它们带来了许多其他因素(称为辅因)。其中一些辅因子修饰覆盖DNA的蛋白质，另一些则增加转录因子与DNA的接触，它们共同直接参与激活或灭活基因。在这个项目中，我们将确定帮助转录因子Ascl1激活产生神经元所需的基因的辅因子。我们还将确定防止促进其他类型细胞生成的基因不适当激活的辅助因素。我们成年人的大脑中包含的干细胞非常少，这意味着它们从脑损伤和疾病中恢复的能力有限。了解神经干细胞产生神经元的机制可以帮助我们找到替代丢失的脑细胞的方法。这可以通过激活驻留的干细胞或将非脑细胞(例如皮肤细胞)转化为神经元来实现。在任何一种情况下，这些细胞都可以被移植或用于测试药物治疗神经系统疾病的能力，因此有可能为各种目前无法治疗的疾病提供治疗方案。该项目将通过确定帮助大脑干细胞生成更多神经元的方法来帮助这一努力。

The purpose of this project is to better understand how stem cells decide whether to multiply or to generate nerve cells. Stem cells are the crucial progenitor cells that generate all the specialized cells that form the organs in the embryo. They are also present in adult organs where they are required for maintenance and repair. Each organ has its own stem cells that generate the particular cell types of that organ. In medicine, stem cells can be used to replace cells that are damaged in diseases; for example blood stem cells are used to treat leukemias. In order to extend their usage to the treatment of other diseases, we must learn much more about how stem cells work. In particular we need to better understand the process by which a stem cell becomes specialised to generate one kind of cell rather than another. In this project, we will study how stem cells of the nervous system (called neural stem cells) become specialized in the generation of nerve cells (neurons). This process involves a profound change in the set of genes that are active: genes that present in stem cells are shut down, while genes characteristic of neurons become active. Gene activity is controlled by proteins called transcription factors. One of the main transcription factors that controls the generation of the neurons of our brains is called Ascl1. The primary purpose of this project is to understand how Ascl1 changes the set of active genes in neural stem cells so that these cells generate new neurons.Transcription factors work by binding to DNA near the genes they activate. They bring with them a multitude of other factors (called cofactors). Some of these cofactors modify the proteins that coat the DNA, others increase the contact of transcription factors with the DNA, and together they are directly involved in activating or inactivating genes. In this project, we will identify the cofactors that help the transcription factor Ascl1 activate the genes required to generate neurons. We will also identify the cofactors that prevent the inappropriate activation of genes that promote the generation of other kinds of cells. Our adult brains contain very few stem cells, which means they are limited in their ability to recover from brain damage and disease. Understanding the machinery that makes neural stem cells produce neurons can help us develop ways to replace lost brain cells. This can be done either by activating the resident stem cells, or transforming non-brain cells (e.g. skin cells) into neurons. In either case, these can then be transplanted or used to test drugs for their ability to treat neurological diseases, and hence have the potential to offer therapeutic solutions to a variety of currently untreatable conditions. This project will help in this endeavour by identifying ways to help stem cells of the brain generate more neurons.