Enteric Neural Stem Cell Loss with Aging: Role of Immune Cells and Inflammation

 描述(由申请人提供)：衰老导致胃肠功能的生理变化，导致许多与年龄相关的疾病。这些疾病的病因可能是多因素的，但肠道神经系统(ENS)中神经元的丢失和退化可能起到一定作用。这项拟议的研究是基于这样一个发现，即与年龄相关的认知能力下降可能是由于与中枢神经系统炎症有关的神经干细胞的丧失。虽然目前尚不清楚肠神经干细胞(ENSCs)的衰退是否会导致肠道神经元随着年龄的增长而丧失，但ENSCs参与神经发生的发现支持这一解释。有趣的是，Foxo3，一种与人类长寿有关的转录因子，最近被发现在包括克罗恩病和类风湿性关节炎在内的炎症性疾病中发挥作用。髓系细胞中Foxo3信号的缺失被发现增加了IL-6的产生，并推动了炎症。根据初步数据，随着年龄的增长，ENS微环境中Foxo3表达的下降和促炎细胞因子的上升，推测衰老增加了炎症，这是由于髓系细胞中Foxo3信号的减少，进而通过功能ENSCs的减少而导致与年龄相关的ENS障碍。这一假设将通过两种方式得到解决。首先，我们将研究FOXO_3在ENS中年龄依赖性炎症中的作用。具体地说，研究人员将评估1)人类和小鼠组织中的炎性变化(与炎性细胞因子和免疫细胞有关)是否随着年龄的增长而增加，2)髓系细胞中的Foxo3表达是否随着年龄的增长而下降，以及3)基因诱导的Foxo3缺失是否会导致炎症随着年龄的增长过早增加。其次，研究人员将研究Foxo3的调节是否会介导随着年龄的增长而失去功能性ENSCs和神经元。具体地说，研究人员将评估1)Foxo3缺乏是否会导致ENSCs功能过早衰退和肠道神经元随年龄增长而丧失；2)Foxo3缺乏是否尤其是免疫细胞缺乏导致这种下降。这项拟议研究的成功完成将回答有关ENS与年龄相关的变化机制的几个关键问题，包括1)炎症是否在人类和小鼠的ENS与年龄相关的破坏中发挥作用，2)Foxo3信号的变化与年龄相关的炎症有关，以及3)炎症导致ENSCs功能丧失，从而干扰受损组织的修复和恢复活力。这项提案将提供免疫调节疗法在年龄相关性胃肠道疾病中发挥作用的概念证据。

 DESCRIPTION (provided by applicant): Aging causes physiologic changes in gastrointestinal intestinal function that contribute to many age-related disorders. The etiology of these disorders is likely multifactorial, but loss and degeneration of neurons in the enteric nervous system (ENS) likely plays a role. The proposed studies are predicated on the finding that age- associated cognitive decline is likely due to loss of neural stem cells related to central nervous system inflammation. While unknown whether a decline in enteric neural stem cells (ENSCs) contributes to loss of enteric neurons with aging, the discovery that ENSCs are involved in neurogenesis supports this interpretation. Interestingly, Foxo3, a transcription factor linked to longevity in humans was recently found to play a role in inflammatory disorders including Crohn's disease and Rheumatoid arthritis. Loss of Foxo3 signaling in myeloid cells was found to increase IL-6 production and drive inflammation. Based on preliminary data which found both a decline in Foxo3 expression and rise in proinflammatory cytokines in the ENS microenvironment with aging, it is posited that aging increases inflammation due to reduction in Foxo3 signaling in myeloid cells which in turn causes age-related ENS disturbances via a decline in functional ENSCs. This hypothesis will be addressed in two ways. First, the role of Foxo3 in age-dependent inflammation in the ENS will be examined. Specifically, the investigators will assess 1) whether inflammatory changes (with respect to inflammatory cytokines and immune cells) increase with aging in human and mouse tissue, 2) whether Foxo3 expression in myeloid cells declines with aging, and 3) if genetically induced Foxo3 deletion causes premature rise in inflammation with aging. Second, the investigators will examine whether modulation of Foxo3 mediates loss of functional ENSCs and neurons with aging. Specifically, the investigators will evaluate 1) if Foxo3 deficiency causes premature decline in functional ENSCs and enteric neuronal loss with aging and 2) whether Foxo3 deficiency particularly in immune cells is responsible for this decline. Successful completion of the proposed research will answer several key questions regarding the mechanism of age-related changes of the ENS including whether 1) inflammation plays a role in age-related disruption of the ENS in humans and mouse, 2) changes in Foxo3 signaling is responsible for age-dependent inflammation, and 3) inflammation causes loss of functional ENSCs thereby interfering with repair and rejuvenation of damaged tissue. This proposal will provide a proof of concept that immunomodulatory therapies have a role in age- associated gastrointestinal disorders.