Regulation of Neurogenesis and Cognition by Systemic Age-Related Immune Factors

描述(申请人提供)：干细胞一直是众多科学努力的焦点，因为它们有潜力促进组织修复，从退行性疾病中再生，并改善与年龄相关的器官功能障碍。利用干细胞逆转正常衰老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。在中枢神经系统中，由于认知障碍的相关发病以及神经退行性疾病(如阿尔茨海默病)缺乏神经修复，因此研究衰老对神经干细胞/祖细胞(NPC)功能的影响尤其令人感兴趣。在我的博士工作中，我发现在老化的全身环境中发生的分子变化对NPC的功能和认知具有负面调节作用。此外，我确定了系统免疫因子的一个子集-2-微球蛋白(B2M)、CCL11和CCL2-作为神经发生和认知功能的潜在调节因子。有趣的是，免疫信号在成人神经发生的负性调节中起着关键作用。因此，这项应用的目的是研究在衰老的全身环境中免疫相关分子的变化如何调节NPC功能和相关的认知过程。具体地说，我的假设是，系统性的年龄相关免疫因素通过直接或间接地通过常驻免疫细胞抑制NPC的功能，损害了神经发生和认知过程。我将从三个方面阐述这一假说：1.确定全身年龄相关免疫因子在体外对鼻咽癌功能的直接和间接影响；2.在体内检测全身年龄相关免疫因子对神经发生和认知功能的直接影响；3.在体内探讨由居民免疫细胞介导的全身年龄相关免疫因子对神经发生和认知功能的间接影响。最终，我希望通过研究NPC功能损害的细胞和分子机制，我们可以更好地了解如何通过利用旧大脑中剩余的潜在可塑性来改善与年龄相关的认知功能障碍。

DESCRIPTION (provided by applicant): Stem cells have been the focus of numerous scientific endeavors due to their potential for mediating enhanced tissue repair, regeneration from degenerative diseases, and amelioration of age-related organ dysfunction. The possibility of harnessing stem cells to reverse normal aging raises the question as to how the aging process modulates tissue specific stem cell activity. In the central nervous system, investigating the effect of aging on neural stem/progenitor cell (NPC) function 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. During my doctoral work, I discovered that molecular changes occurring in the aging systemic milieu negatively regulate NPC function and cognition. Furthermore, I identified a subset of systemic immune factors - ¿2-Microglobulin (B2M), CCL11 and CCL2 -, as potential regulators of neurogenesis and cognitive function. Interestingly, immune signaling has emerged as a key player in the negative regulation of adult neurogenesis. Thus, the goal of this application is to investigate how immune-related molecular changes in the aging systemic milieu regulate NPC function and associated cognitive processes. Specifically, my hypothesis is that systemic age-related immune factors impair neurogenesis, and cognitive processes, by both inhibiting NPC function directly and indirectly via resident immune cells. I will address this hypothesis in three aims: 1.To determine the direct versus indirect effect of systemic age-related immune factors on NPC function in vitro, 2. To examine the direct effect of systemic age-related immune factors on neurogenesis and cognitive function in vivo, 3. To explore the indirect effect of systemic age-related immune factors mediated by resident immune cells on neurogenesis and cognitive function in vivo. Ultimately, I hope that by investigating the cellular and molecular mechanisms underlying impairments in NPC function, we can better understand how to ameliorate age-related cognitive dysfunction by harnessing the latent plasticity remaining within the old brain.