Regulation of Neural Stem Cells by Changes in the Aging Systemic Environment

描述(申请人提供)：哺乳动物的衰老与组织特异性干细胞的功能和再生能力的下降有关。在成人中枢神经中，这些功能干细胞/祖细胞(NSC)的年龄相关性下降，以及随后的神经发生，与嗅觉和认知功能(如学习和记忆)的损害有关。有趣的是，生物体系统环境的变化，如通过增加锻炼和限制饮食而引起的变化，已被证明部分缓解了这种细胞衰退，并增强了学习和记忆。最近的开创性工作在细胞水平上研究了神经干细胞衰老的内在分子机制，但在阐明衰老过程中系统分子环境的变化如何损害依赖年龄的神经干细胞功能方面仍存在空白。因此，这项提议的目的是开始阐明衰老有机体中的系统性变化如何改变成年大脑中NSC的功能。具体地说，我的假设是，在衰老的大脑中，系统分子环境中年龄相关的变化调节着成年神经干细胞的维持和潜在的恢复活力。我将从三个方面阐述这一假说：1.确定与NSC维持和神经再生的年龄相关性下降相关的系统可溶信号蛋白的分子谱；2.确定年轻和老年系统环境中的分子变化如何影响体内年龄相关的NSC功能；3.确定个体衰老分子谱的变化如何改变体外NSC的功能。这些研究最终将深入了解衰老过程损害神经干细胞功能的机制，并可能确定对抗受损神经修复的新治疗靶点。干细胞一直是众多科学努力的焦点，因为它们有可能促进组织修复，从退行性疾病中再生，以及改善由于正常衰老而导致的器官功能障碍。利用干细胞进行治疗以对抗与年龄相关的再生限制的可能性提出了一个问题，即衰老过程如何调节组织特异性干细胞的活动，以及它们无法维持衰老有机体内器官的结构和功能。在此背景下，这些实验将深入了解衰老对大脑中NSC功能的影响，这是特别令人感兴趣的，因为认知障碍的相关发病和神经修复的缺乏，以应对神经退行性疾病，如阿尔茨海默病。

DESCRIPTION (provided by applicant): Aging in mammals is associated with a decline in the function and regenerative capacity of tissue specific stem cells. In the adult central nervous the age-related decline of these functional stem/progenitor cells (NSC), and subsequently neurogenesis, is correlated with impairments in olfaction and cognitive functions such as learning and memory. Interestingly, changes to the systemic milieu of an organism, such as those induced through increased exercise and dietary restriction, have been shown to partially mitigate this cellular decline, as well as enhance learning and memory. Recent pioneering work has examined intrinsic molecular mechanisms that underlie NSC aging at the cellular level, however a gap still exists in elucidating how age-dependent NSC function is impaired by changes in the systemic molecular environment during aging. The purpose of this proposal is therefore to begin to elucidate how systemic changes in an aging organism alters the functionality of NSC in the adult brain. Specifically, my hypothesis is that age-dependent changes in the systemic molecular environment regulate the maintenance and potential rejuvenation of adult NSC in the aging brain. I will address this hypothesis in three aims: 1. To identify a systemic molecular profile of soluble signaling proteins that correlate with age-dependent decline in NSC maintenance and neural regeneration, 2. To determine how molecular changes in the young and old systemic environments affect age-dependent NSC function in vivo, and 3. To determine how individual changes in the aging molecular profile alter NSC function in vitro. These studies will ultimately provide insight into mechanisms by which the aging process impairs NSC function and may identify novel therapeutic targets for combating impaired neural repair. Stem cells have been the focus of numerous scientific endeavors due to their potential for mediating enhanced tissue repair, regeneration from degenerative diseases, and the amelioration of organ dysfunction due to normal aging. The possibility of harnessing stem cells for therapeutics to combat age-related regenerative limitations raises the question as to how the aging process modulates tissue specific stem cell activity, as well as their inability to maintain both the structure and function of organs within an aging organism. In this context these experiments will provide insight into the effect of aging on NSC function in the brain which is of particular interest due to the associated onset of cognitive impairments and lack of neural repair in response to neurodegenerative diseases such as Alzheimer's disease.