Regulation and function of the stem cell activation factor Ascl1 in constitutive and injury-induced adult neurogenesis

这个项目的目的是了解为什么只在大脑的特定区域产生新的神经细胞，以及为什么损伤不能在其他大脑区域修复。神经细胞是由称为干细胞的特殊细胞产生的，这种细胞保留了胚胎中细胞的特性，以分裂和产生各种类型的专门细胞。干细胞只存在于大脑的有限区域，在那里它们一生都在分裂，产生新的神经细胞。我们已经发现了一种名为Ascl1的蛋白质，它可以刺激干细胞的分裂，因此对产生新的神经细胞很重要。我们在瑞典卡罗林斯卡研究所的合作者还发现，中风后在另一个脑区和一种名为神经胶质细胞的不同类型的细胞中也存在相同的Ascl1蛋白。其中一些胶质细胞在中风后存在Ascl1时表现为干细胞，因为它们分裂并产生新的神经细胞，但另一些细胞对Ascl1的存在没有反应，无法产生神经细胞。为了帮助大脑修复中风造成的损伤，显然有必要改善神经胶质细胞对损伤的反应，并帮助它们变得更像干细胞。为此，我们需要更好地了解Ascl1是如何工作的。通过这个项目，我们想首先了解为什么Ascl1在中风后存在于干细胞和一些神经胶质细胞中，而在另一些细胞中不存在。因此，我们将研究控制Ascl1发现的脑细胞的分子。其次，我们想知道为什么当Ascl1存在于胶质细胞中时，一些细胞表现为干细胞并分裂，而另一些细胞对Ascl1的存在没有反应并继续表现为正常神经胶质细胞。ASCL1是一种转录因子，这意味着它控制着存在ASCL1的细胞中许多基因的活性，而这些基因反过来又控制着细胞的行为，如分裂。因此，我们将研究在对Ascl1做出反应的干细胞样神经胶质细胞中由Ascl1控制的基因，我们将找出为什么在其他神经胶质细胞中相同的基因不受Ascl1控制。我们希望我们的研究能够更好地理解大脑对中风等损伤的反应，以及为什么它用新细胞取代丢失的神经细胞的能力有限。从长远来看，我们希望对中风对胶质细胞的影响有足够的了解，以帮助设计出将更多的胶质细胞转化为干细胞并帮助大脑自我修复的治疗方法。

The purpose of this project is to understand why new nerve cells are produced only in particular areas of the brain and why injuries cannot be repaired in other brain areas. Nerve cells are produced by special cells called stem cells that retain the properties of cells in the embryo to divide and produce various types of specialized cells. Stem cells are only found in limited areas of the brain where they divide throughout life to produce new nerve cells. We have found a protein called Ascl1 that stimulates the divisions of the stem cells and is therefore important for the production of new nerve cells. Our collaborators at the Karolinska Institute in Sweden have also found that the same protein Ascl1 is also present after a stroke in another brain region and in a distinct type of cells called glial cells. Some of these glial cells behave like stem cells when Ascl1 is present after stroke, as they divide and produce new nerve cells, but others do not react to the presence of Ascl1 and fail to produce nerve cells. To help the brain repair the damages caused by strokes, there is clearly a need to improve how glial cells react to the injury and to help them become more like stem cells. For this, we need to understand better how Ascl1 works. With this project, we want first to understand why Ascl1 is present in stem cells and in some glial cells after a stroke but not in others. We will therefore study the molecules that control in which brain cells Ascl1 is found. Second, we want to understand why, when Ascl1 is present in glial cells, some behave like stem cells and divide while other do not react to the presence of Ascl1 and continue to behave like normal glial cells. Ascl1 is a transcription factor, which means that it controls the activity of many genes in the cells where it is present, and these genes in turn control the behavior of the cells such as their divisions. We will therefore examine the genes that are controlled by Ascl1 in stem cell-like glial cells that respond to Ascl1 and we will find out why the same genes are not controlled by Ascl1 in other glial cells.We expect our research to lead to a better understanding of how the brain reacts to injuries such as strokes and why it has a limited ability to replace the nerve cells lost with new cells. In the longer term, we hope to have learned enough of the effect of stroke on glial cells to help devise treatments that convert more glial cells into stem cells and help the brain repair itself.