Mechanisms Underlying the Survival of Adult Generated Neurons

大脑拥有一种与生俱来的能力，可以通过在整个成年期分裂神经前体细胞来产生新的神经元。令人惊讶的是，在生成的数千个细胞中，绝大多数随着成熟而死亡，因此前体细胞的增殖只会导致少数新生成的神经元。为了操纵或促进神经元在大脑中存活并发出信号，必须更好地了解调控鼻咽癌存活的分子途径。*这项拨款中提出的研究源于我们的发现，即一种名为细胞周期蛋白依赖性激酶5(CDK5)的蛋白质对神经前体细胞的生存至关重要。这导致我们的实验室在细胞内寻找组成CDK5介导的生存途径的其他蛋白质。我们的数据表明，CDK5是前体细胞生存所必需的，因为它与一种名为Bcl-2的蛋白质相互作用，这种蛋白质在称为细胞凋亡的细胞死亡过程中抵消细胞死亡。BCL-2与一种名为Beclin1的蛋白质相互作用，Beclin1对调节称为自噬的细胞内清除过程非常重要，自噬也可以通过与细胞凋亡的相互作用来调节细胞死亡。因此，我们有一系列一致的证据支持神经前体细胞在成人大脑中的生存需要依赖于CDK5的凋亡和自噬途径的调节。为了验证这一假设，我们将使用转基因小鼠模型和病毒基因转移到小鼠脑内，以便我们可以从神经前体细胞中移除或操纵CDK5、Bcl-2或Beclin1的表达，并确定这些途径如何在复杂的大脑环境中调节这些细胞的生存。*这些结果为神经前体细胞如何存活并发育为大脑中的新神经元提供了新的见解，并进一步加深了我们对细胞凋亡和自噬之间复杂关系的理解，自噬控制着细胞的生存或死亡。我们的发现旨在向世界提供所需的知识，使治疗方法的开发能够潜在地改变许多疾病治疗中的新神经元，这将为加拿大人带来巨大的好处。此外，这项工作将帮助加拿大招募和留住训练有素的科学家，并培养下一代神经科学家，以解决与大脑和思维有关的许多未知问题。

The brain possesses an innate ability to generate new neurons from dividing neural precursor cells throughout adulthood. Surprisingly, of the thousands of cells that are generated, the vast majority of them die as they mature, thus proliferation of precursor cells only results in a few newly generated neurons. In order to manipulate or promote neurons to survive and signal within the brain, it is imperative to better understand the molecular pathways that regulate NPC survival. ***The studies proposed in this grant, arises from our discovery that a protein called cyclin dependent kinase 5 (Cdk5) is essential for the survival of neural precursor cells. This led our lab into the search for other proteins within the cells that make up the Cdk5-mediated survival pathway. Our data suggests that Cdk5 is required for survival of precursor cells due to its interaction with a protein called Bcl-2, which counteracts cell death, in a cell death process called apoptosis. Bcl-2 interacts with a protein called Beclin1, which is important for regulating an intracellular cleaning process called autophagy, which can also regulate cell death through its interaction with apoptosis. Thus together we have converging lines of evidence to support that the survival of neural precursor cells in the adult brain requires Cdk5-dependent regulation of the apoptotic and autophagic pathways. To test this hypothesis we will use transgenic mice models and viral gene transfer into the mouse brain, so that we can remove, or manipulate the expression of Cdk5, Bcl-2 or beclin1 from the neural precursor cells and determine how these pathways interact in regulating survival of these cells within the complex environment of the brain. ***These results provide novel insight into how neural precursor cells survive to develop into a new neurons in the brain, as well as further our understanding of the complex relationship between apoptosis and autophagy that controls whether cells survive or die. Our findings aim to provide the world with the knowledge required to enable development of treatments that could potentially modify the new neurons in the treatment of many diseases, which would provide enormous benefit to Canadians. In addition this work will benefit Canada by helping recruit and retain highly trained scientists, as well as train the next generation of neuroscientists to tackle the many unknowns related to the brain and mind.********