Mechanisms Underlying the Survival of Adult Generated Neurons

成体神经元存活的机制

• 批准号: RGPIN-2015-03638
• 负责人: Lagace, Diane
• 金额: $ 2.4万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=612472
• 关键词: Mechanisms; Underlying; Survival; Adult; Generated

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.

大脑拥有一种天生的能力，可以在整个成年期从分裂的神经前体细胞中产生新的神经元。令人惊讶的是，在生成的数千个细胞中，绝大多数细胞在成熟时死亡，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和发出信号，必须更好地了解调节NPC存活的分子途径。 在这项研究中，我们发现一种称为细胞周期蛋白依赖性激酶5（Cdk 5）的蛋白质对神经前体细胞的生存至关重要。这使得我们的实验室开始寻找细胞内构成Cdk 5介导的生存途径的其他蛋白质。我们的数据表明，Cdk 5是前体细胞生存所必需的，因为它与一种称为Bcl-2的蛋白质相互作用，这种蛋白质在称为凋亡的细胞死亡过程中抵消细胞死亡。Bcl-2与一种名为Beclin 1的蛋白质相互作用，Beclin 1对调节称为自噬的细胞内清洁过程很重要，自噬也可以通过与凋亡的相互作用调节细胞死亡。因此，我们有汇聚线的证据，以支持在成人大脑中的神经前体细胞的生存需要Cdk 5依赖性调节的凋亡和自噬途径。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大脑中，这样我们就可以从神经前体细胞中去除或操纵Cdk 5，Bcl-2或beclin 1的表达，并确定这些途径如何相互作用，调节这些细胞在大脑复杂环境中的存活。 这些结果为神经前体细胞如何存活发育成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，这些关系控制着细胞的存活或死亡。我们的研究结果旨在为世界提供所需的知识，以开发可能在治疗许多疾病中改变新神经元的治疗方法，这将为加拿大人带来巨大的利益。此外，这项工作将有助于招募和留住训练有素的科学家，并培养下一代神经科学家来解决与大脑和思维有关的许多未知问题。