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

肠道神经干细胞随衰老而丧失：免疫细胞和炎症的作用

• 批准号: 8842824
• 负责人: Aida Habtezion
• 金额: $ 20.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842824
• 关键词: Address; Affect; Age; Age-associated memory impairment; Aging; Anorexia; Biological Neural Networks; Cells; Chimera organism; Constipation; Controlled Study; Crohn' s disease; Data; Dendritic Cells; Disease; Elderly; Enteral; Enteric Nervous System; Etiology; Family; Fecal Incontinence; Flow Cytometry; Gastrointestinal Diseases; Hematopoietic; Human; Immune; Immunophenotyping; Impaired cognition; Inflammation; Inflammatory; Injury; Interleukin-6; Intestines; Knockout Mice; Lead; Link; Longevity; Mediating; Mus; Myelogenous; Myeloid Cells; Nerve Degeneration; Neuraxis; Neurons; Physiological; Play; Population; Production; Quality of life; Rejuvenation; Reporting; Research; Research Personnel; Rheumatoid Arthritis; Role; Signal Transduction; Societies; Testing; Tissues; age related; base; cytokine; functional loss; gastrointestinal; gastrointestinal function; macrophage; member; nerve stem cell; neurogenesis; neuron loss; premature; prevent; public health relevance; repaired; transcription factor

 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.

 描述（由申请人提供）：衰老引起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，但肠神经系统（ENS）中神经元的丢失和变性可能起作用。拟议的研究是基于这样的发现，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相关的神经干细胞的丧失。虽然尚不清楚肠神经干细胞（ENSC）的下降是否会导致肠神经元随着衰老而丢失，但ENSC参与神经发生的发现支持了这一解释。有趣的是，Foxo 3是一种与人类长寿相关的转录因子，最近发现它在炎症性疾病中发挥作用，包括克罗恩病和风湿性关节炎。发现髓样细胞中Foxo 3信号传导的缺失增加IL-6的产生并驱动炎症。基于发现ENS微环境中Foxo 3表达随衰老下降和促炎细胞因子升高的初步数据，推测衰老由于骨髓细胞中Foxo 3信号传导的减少而增加炎症，这反过来又通过功能性ENSC的下降引起年龄相关的ENS紊乱。这一假设将以两种方式加以论述。首先，将检查Foxo 3在ENS中的年龄依赖性炎症中的作用。具体而言，研究人员将评估1）人类和小鼠组织中的炎症变化（关于炎性细胞因子和免疫细胞）是否随着衰老而增加，2）骨髓细胞中的Foxo 3表达是否随着衰老而下降，以及3）遗传诱导的Foxo 3缺失是否会导致炎症过早增加。其次，研究人员将研究Foxo 3的调节是否介导了功能性ENSC和神经元的衰老损失。具体而言，研究人员将评估1）Foxo 3缺乏是否会导致功能性ENSC过早下降和肠神经元随年龄增长而丢失，以及2）Foxo 3缺乏（特别是免疫细胞中的Foxo 3缺乏）是否会导致这种下降。成功完成拟议的研究将回答有关ENS年龄相关变化机制的几个关键问题，包括1）炎症是否在人类和小鼠ENS的年龄相关破坏中发挥作用，2）Foxo 3信号传导的变化是年龄依赖性炎症的原因，3）炎症导致功能性ENSC的丧失，从而干扰受损组织的修复和再生。该提案将提供免疫调节治疗在年龄相关胃肠道疾病中发挥作用的概念证明。