Regulation of adult neurogenesis during aging

描述（由申请人提供）：在所有哺乳动物（包括人）的成年中枢神经系统（CNS）中存在神经祖细胞/干细胞，这提高了通过激活内源性神经祖细胞/干细胞或移植体外扩增的神经干细胞及其后代来替代受损或丢失的神经元的可能性。由于大多数退行性神经系统疾病和损伤发生在老年人群中，因此更好地了解神经干细胞如何与老年大脑中的局部环境相互作用对于开发基于干细胞的治疗策略至关重要。成年人海马齿状回的神经发生，一个参与学习和记忆的区域，已经被证明随着年龄的增长而减少。这种减少是否反映了神经祖细胞/干细胞内在特性的变化和/或衰老过程中局部环境的变化尚不清楚。虽然年轻成年啮齿动物的神经干细胞可以在培养和体内产生具有成熟CNS神经元基本特性的功能性神经元，但尚不清楚老年神经干细胞是否可以产生功能性神经元以及老年大脑是否可以支持功能性神经发生。衰老与大脑炎症和氧化的增加有关。CNS炎症最近被证明负调节成人神经发生。我们以前已经表明，炎症改变神经细胞的鞘脂和固醇含量，破坏脂筏的结构和功能，这反过来又可以通过干扰细胞信号来改变神经细胞功能。我们已经从年轻的成年和老年大鼠的海马中分离出神经祖细胞，并开发了在培养和体内研究其增殖、命运决定、功能和电生理特性的方法。在这个项目中，我们建议确定的作用，内在与外在机制在调节功能性成年神经发生的啮齿动物模型老化的顺序步骤。特别是，我们将使用药理学和饮食的操作，以修改氧化还原平衡，鞘脂和甾醇代谢和定量比较年轻的成年人和老年人海马神经祖细胞/干细胞在体外和体内的属性。

DESCRIPTION (provided by applicant): The existence of neural progenitor/stem cells in the adult central nervous system (CNS) of all mammals, including humans, raises the possibility to replace damaged or lost neurons by activation of endogenous neural progenitor/stem cells or transplantation of in vitro expanded neural stem cells and their progeny. Since most degenerative neurological diseases and injuries occur in the aged population, better understanding of how neural stem cells interact with their local environment in the aged brain will be essential to develop strategies for stem cell based therapies. Adult neurogenesis in the dentate gyrus of the hippocampus, a region involved in learning and memory, has been shown to decrease with increasing age. Whether this reduction reflects changes in the intrinsic properties of neural progenitor/stem cells and/or changes of the local environment during aging is unknown. While neural stem cells of young adult rodents can generate functional neurons with essential properties of mature CNS neurons both in culture and in vivo, it is not known if aged neural stem cells can generate functional neurons and whether the aged brain can support functional neurogenesis. Aging is associated with increases of brain inflammation and oxidation. CNS inflammation was recently shown to negatively regulate adult neurogenesis. We have previously shown that inflammation modifies the sphingolipid and sterol content of neural cells and disrupts the structure and function of lipid rafts, which in turn can modify neural cell function by perturbation of cellular signaling. We have isolated neural progenitors from the hippocampus of both young adult and aged rats and developed methods to investigate their proliferation, fate determination, functional and electrophysiological properties both in culture and in vivo. In this project, we propose to determine the roles of intrinsic vs. extrinsic mechanisms in regulating the sequential steps of functional adult neurogenesis in a rodent model of aging. In particular, we will use pharmacological and dietary manipulations to modify redox balance, sphingolipid and sterol metabolism and quantitatively compare the properties of neural progenitor/stem cells of young adult and aged hippocampus both in vitro and in vivo.