Epigenetic mechanisms regulating pluripotency from embryonic to adult neurogeneisis

神经系统疾病是最具破坏性的疾病之一，因为大脑在自我修复方面做得非常糟糕。在大多数情况下，无法产生新的神经细胞来取代受损组织。随着人口平均年龄的增加，阿尔茨海默氏症、帕金森氏症和中风等疾病将给个人、家庭和社会带来越来越沉重的负担。随着脑干细胞的发现和对它们如何控制的了解的增加，治疗解决方案的希望已经出现。干细胞在大脑的两个特定区域被发现，并在这些受限区域继续产生神经细胞。我们的目标是了解如何加强这一过程，并诱使其在整个大脑中具有更广泛的相关性。在过去的十年里，包括我们在内的世界各地的实验室(北京的沈阳，牛津的Szele)发现了许多刺激干细胞在正常发育期间生长的分子，以及刺激它们修复受损大脑的分子。利用这一知识，我们将能够开发出模仿这些分子的药物，从而刺激干细胞的生长，用于大脑修复。由于成人大脑的修复在概念上类似于大脑的发育，我们也试图了解调控人类胚胎干细胞(HESC)产生神经细胞的基本分子机制。令人惊讶的是，hESC可以在细胞培养皿中培养，使我们能够发现增加神经细胞产生的分子。同样，成人脑干细胞可以在细胞培养中培养，以研究其神经细胞的生成。在这笔拨款中，我们将使用并比较这两种方法，以实现我们增加干细胞来源的神经细胞生成的目标。20世纪的大多数研究揭示了单个分子如何一次一个地调节干细胞。在本世纪，重点发生了转移，该领域现在正在寻求了解分子如何协同工作来协调干细胞神经的产生。这是一个明智的转变，因为通常需要数十到数百个分子来协调干细胞神经的生成。但是，这么多分子是如何同时在同一空间以如此协调的方式进行调控的呢？答案类似于指挥家组织管弦乐队的方式：她可以增加弦乐部分的音量，同时抑制喇叭。所谓的“表观遗传”机制通过导致一些分子被强调，一些分子被抑制来协调数十到数百个分子。表观遗传机制可以完全打开或关闭分子，也可以更微妙地打开或关闭分子。重要的是，它们在干细胞中这样做，从而导致细胞增殖或转变为神经细胞。在我们的实验室中，我们研究了表观遗传机制如何增加胚胎干细胞(沈阳，北京)和成人脑干细胞(Szele，牛津)的神经细胞产量。在这个合作项目中，我们将寻求了解胚胎和成人中相同的分子在多大程度上控制神经细胞的产生。我们还将利用这一新的分子知识来增加中风模型中干细胞介导的神经细胞的产生。婴儿的大脑比成年人和老年人的可塑性要高得多。然而，在脑瘫等疾病中，即使是婴儿的大脑也不能完全修复自己。因此，我们还将试图了解表观遗传分子如何促进干细胞介导的婴儿脑瘫模型的修复。我们的首要目标是最终利用这些信息增加干细胞产生的神经细胞。这一令人兴奋的再生医学分支是治疗神经疾病未来的最大希望之一。

Neurological diseases are amongst the most devastating since the brain does a very poor job in healing itself. In the large majority of cases, new nerve cells cannot be produced to replace injured tissue. With the increase in the population's average age, diseases such as Alzheimer's, Parkinson's and stroke will take an increasingly burdensome toll on individuals, families and society. Hope for a therapeutic solution has arisen with the discovery of brain stem cells and increased understanding of how they are controlled. Stem cells are found in two specific regions of the brain and continue to generate nerve cells in those restricted areas. Our goal is to understand how to enhance this process and entice it to be of more general relevance throughout the brain. In the past decade, laboratories around the world including ours (Shen in Beijing, Szele in Oxford) have discovered many molecules that stimulate stem cells to grow during normal development and molecules that stimulate them to repair a damaged brain. Use of this knowledge will allow us to develop medicines that mimic these molecules and thereby stimulate the growth of stem cells for brain repair. Since the repair of the adult brain is conceptually similar to the development of the brain, we also seek to understand fundamental molecular mechanisms regulating the generation of nerve cells from human embryonic stem cells (hESC). Amazingly, hESC can be grown in cell culture dishes, allowing us to discover molecules that increase nerve cell production. Similarly, adult brain stem cells can be grown in cell culture to study their generation of nerve cells. In this grant, we will use and compare both approaches in our goal to increase stem cell-derived nerve cell generation.Most research in the 20th century has uncovered how individual molecules regulate stem cells one at a time. In this century, a shift in emphasis has occurred, and the field is now seeking to understand how molecules work together to coordinate stem cell nerve generation. This is an intelligent shift since dozens to hundreds of molecules usually are required to coordinate stem cell nerve generation. But how are so many molecules regulated in the same space and at the same time in such a coordinated way? The answer is in a fashion analogous to how a conductor organizes an orchestra: she may increase the loudness of the string section whilst repressing the horns. So-called "epigenetic" mechanisms coordinate dozens to hundreds of molecules by causing some to be emphasized and some to be repressed. Epigenetic mechanisms can turn molecules completely on or off, or they can more subtly turn them up or down. Importantly, they do this in stem cells and thereby cause the cells to either proliferate or to turn into nerve cells.In our laboratories, we study how epigenetic mechanisms increase nerve cell production from embryonic stem cells (Shen, Beijing) and from adult brain stem cells (Szele, Oxford). In this collaborative project, we will seek to understand the extent to which the same molecules govern nerve cell production in the embryo as we as in the adult. We will also use this novel molecular knowledge to increase stem cell-mediated nerve cell production in a model of stroke. Brains of infants have a far higher plasticity than those in the adult and aged population. However, even infant brains do not completely repair themselves in diseases such as cerebral palsy. Thus, we will also seek to understand how epigenetic molecules enhance stem cell-mediated repair of a model of infant cerebral palsy.Our overarching goal is to eventually use this information to increase nerve cell production from stem cells. This exciting branch of regenerative medicine is one of the best hopes for the future of treating neurological disorders.