Investigation of the cellular and molecular mediators of adult neurogenesis

成人神经发生的细胞和分子介质的研究

• 批准号: RGPIN-2019-07062
• 负责人: Scott, Angela
• 金额: $ 2.4万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684798
• 关键词: Investigation; cellular; molecular; mediators; adult

Regeneration is often referred to as the 'holy grail' in scientific and medical research and is truly a fascinating feat in the central nervous system (CNS). Indeed, the successful replacement or regrowth of adult neurons in fully developed and highly integrated circuits is a phenomenon that occurs in only select vertebrate species. Mammals, for example, are generally incapable of adult regeneration and undergo neurogenesis (the birth of new neurons) in only a few restricted regions within the brain. In contrast, adult zebrafish undertake a vigorous regenerative process throughout the brain and spinal cord following CNS injury and maintain many neurogenic regions throughout their lifetime. The molecular factors responsible for neurogenesis and regeneration in this species, and what makes them unique from mammals, are largely unknown. The identification of essential neurogenic factors will provide needed insight into the molecular mechanisms that instruct neurogenesis in adult vertebrates and shed light on the evolutionary differences between natural regenerators' and non-regenerators'. ******Our current knowledge of adult neurogenesis is fragmented and largely derived from studies of the few neurogenic sites within the mammalian brain. In addition, very little is known about the essential intercellular relationships that largely govern adult neurogenesis, particularly those between subtypes of glial cells, and damaged or new neurons. Characterization of neurogenesis in the zebrafish spinal cord, with an emphasis on glial physiology and signaling, will therefore make a novel and important contribution to this field. Our short-term goals will work to address the following fundamental questions: what molecular factors govern regeneration in the zebrafish spinal cord; what homeostatic or neuroprotective roles to glial cells play in this system; and finally, do inflammatory signals associated with injury set the stage for regeneration? Here, we focus on the purinergic signaling family, the most ubiquitous and evolutionarily conserved family of signaling proteins in the CNS, but also the most unknown. We also aim to make direct comparisons to the mammalian microenvironment to gain insight into both the cellular and molecular components that prevent regeneration in this species. These studies offer an important prelude to subsequent, long-term goals aimed at discerning the appropriate choreography of signals that are responsible for regulating neural growth, development and neuroplasticity. Unraveling the cellular and molecular integration that drives these processes in zebrafish will be an invaluable step in understanding the evolutionary diversity of nervous system regeneration. *****

再生通常被称为科学和医学研究中的“圣杯”，是中枢神经系统（CNS）中一项令人着迷的壮举。事实上，在完全发育和高度集成的电路中，成年神经元的成功替换或再生是一种只发生在特定脊椎动物物种中的现象。例如，哺乳动物一般不能再生成人，只在大脑的几个有限区域进行神经发生（新神经元的诞生）。相比之下，成年斑马鱼在中枢神经系统损伤后，在整个大脑和脊髓中进行了强有力的再生过程，并在其一生中维持了许多神经原区。在这个物种中，负责神经发生和再生的分子因素，以及是什么使它们与哺乳动物不同，在很大程度上是未知的。必要神经发生因子的识别将为指导成年脊椎动物神经发生的分子机制提供必要的见解，并阐明自然再生者和非再生者之间的进化差异。******我们目前对成人神经发生的知识是碎片化的，主要来自对哺乳动物大脑中少数神经发生部位的研究。此外，对于在很大程度上控制成人神经发生的基本细胞间关系，特别是神经胶质细胞亚型与受损或新生神经元之间的关系，我们知之甚少。因此，斑马鱼脊髓神经发生的表征，重点是神经胶质生理学和信号传导，将为这一领域做出新的重要贡献。我们的短期目标将致力于解决以下基本问题：什么分子因素控制斑马鱼脊髓的再生；神经胶质细胞在这个系统中扮演什么自我平衡或神经保护的角色；最后，与损伤相关的炎症信号是否为再生奠定了基础？在这里，我们关注嘌呤能信号家族，这是中枢神经系统中最普遍和进化上保守的信号蛋白家族，但也是最不为人知的。我们还旨在与哺乳动物微环境进行直接比较，以深入了解阻止该物种再生的细胞和分子成分。这些研究为后续的长期目标提供了重要的前奏，这些目标旨在识别负责调节神经生长、发育和神经可塑性的信号的适当编排。解开驱动斑马鱼这些过程的细胞和分子整合将是理解神经系统再生进化多样性的宝贵一步。＊＊＊＊＊