Regulation of Adult Neurogenesis by Autophagy

我的NSERC资助的研究项目正在解决是什么监管成人大脑中的成人干细胞如何产生神经元的问题。与关于神经元在大脑形成过程中如何发育的大量知识相比，由于科学进步发现如何分离和操纵成熟大脑中的单个细胞，我们才刚刚开始了解这个过程是如何在成人大脑中发生的。理解这一点很重要，因为必须对成年大脑中神经元是如何产生的有基本的了解，以便在旨在改善大脑功能的同时促进和维持神经元的发育。这项拨款中提出的研究源于我们实验室的发现，即一种称为自噬的过程对成年出生的神经元的生成至关重要。自噬通常被称为相当于房屋清理的细胞，允许去除细胞废物和回收材料，因此是细胞内重要的质量控制功能。我们的发现让我们对成年神经元发育的哪个组成部分产生自噬效应产生了疑问。干细胞中是否需要这种物质才能形成神经元？它会改变新细胞的分裂能力吗？它是否影响为成体生成的细胞提供必要支持的周围细胞？为了提供这些问题的答案，我们创造了新的小鼠模型，使我们能够移除与自噬相关的重要基因ATG5，以研究自噬的丧失如何改变成年神经元的不同发育阶段。我们的实验包括使用最新的技术进步，允许分析处于不同发育阶段的单个细胞内的遗传密码。这种史无前例的分析水平将在细胞发育的每个阶段带来新的见解，以确定自噬调节成年神经元生成的潜在机制。这项研究为成人神经发生和自噬提供了基本的见解。这些研究提供了一个综合的、多水平的分析，将参与自噬的不同主要参与者与成人神经发生的不同阶段的调控以及这一过程中基因表达的变化联系起来。这些研究由实验室内接受尖端、协作和跨越许多学科的培训的不同受训人员领导。这将使受训人员能够实现他们独立的职业发展目标，并赋予他们必要的独特性，使他们成为有价值的、专门的和多才多艺的专家。对加拿大来说，重要的是，这些学生将成为学术界和教育界的下一代领导者，以及快速增长的生物技术和干细胞行业的领导者。

My NSERC funded research program is tackling the question of what regulates how adult stem cells in the adult brain generate neurons. In comparison to the vast amount of knowledge about how neurons develop during the formation of the brain, we have only begun to understand how this process occurs within the adult brain due to scientific advances that have discovered how to isolate and manipulate individual cells within the mature brain. This is important to understand since it is imperative to have fundamental knowledge on how neurons are generated in the adult brain in order to promote and sustain the development of neurons while aiming to improve brain function. The studies proposed in this grant arise from our lab's discovery that a process called autophagy is essential for the generation of adult-born neurons. Autophagy is often called the cellular equivalent of housecleaning, allowing for the removal of cellular waste and recycling of materials, and thus serves as an important intracellular quality control function. Our findings have led us to question which component of adult neuron development does autophagy effects. Is it required in the stem cells that give rise to neurons? Does it alter the ability of the new cells to divide? Does it affect surrounding cells that provide essential support to the adult-generated cells? To provide answers to these questions we have created novel mouse models that have allowed us to remove an essential autophagy related gene called Atg5 in order to examine how loss of autophagy alters the different stages of development of adult neurons. Included in our experiments is the use of recent technical advances allowing for analysis of the genetic code within individual cells at different stages of development. This unprecedented level of analysis will lead to novel insights in each stage of cell development to identify the mechanisms underlying the ability of autophagy to regulate the generation of adult neurons. This research provides fundamental insights into both adult neurogenesis and autophagy. These studies provide an integrated, multi-level analysis that links the different main players involved in autophagy to the regulation of the different stages of adult neurogenesis, as well as changes in gene expression during this process. The studies are being led by a diverse group of trainees within the laboratory receiving training that is cutting-edge, collaborative, and spans many disciplines. This will allow the trainees to achieve their independent career development goals and give them the necessary uniqueness that will make them valuable, specialized and versatile experts. Importantly for Canada, these students will become the next-generation of leaders in academia and education, as well as in the rapidly growing biotechnology and stem cell industry.