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

描述（由申请人提供）：干细胞已成为众多科学研究的焦点，因为它们具有促进组织修复、退行性疾病再生和改善与年龄相关的器官功能障碍的潜力。利用干细胞逆转正常衰老的可能性提出了衰老过程如何调节组织特异性干细胞活性的问题。在中枢神经系统中，研究衰老对神经干/祖细胞（NPC）功能的影响是特别有趣的，因为它与认知障碍的发病有关，并且在对神经退行性疾病（如阿尔茨海默病）的反应中缺乏神经修复。在我的博士工作中，我发现在衰老的系统环境中发生的分子变化对NPC功能和认知产生了负面调节。此外，我确定了一个全身免疫因子子集- 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，免疫信号已成为成人神经发生负调控的关键角色。因此，本应用程序的目的是研究衰老系统环境中免疫相关分子变化如何调节NPC功能和相关认知过程。具体来说，我的假设是，系统性年龄相关免疫因子通过直接或间接地通过常驻免疫细胞抑制鼻咽癌功能，从而损害神经发生和认知过程。我将从三个方面阐述这一假设：1。为了确定年龄相关的全身免疫因子对鼻咽癌体外功能的直接和间接影响。研究年龄相关免疫因子对体内神经发生和认知功能的直接影响。探讨由常驻免疫细胞介导的系统性年龄相关免疫因子对体内神经发生和认知功能的间接影响。最后，我希望通过研究NPC功能受损的细胞和分子机制，我们可以更好地了解如何通过利用老年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.