Identification of enteric Juvenile Protective Factors and their role in stimulating neurogenesis in the adult and ageing Enteric Nervous System

项目摘要/摘要 肠道运动由肠道神经系统(ENS)调节，该系统完全驻留在肠壁内 它由大脑外最大的神经元和神经胶质细胞组成。此前，我们有 提供的证据表明ENS的出生后发育和成年后的维持由不同的 胎-幼表达Sox10和成体表达巢蛋白的肠神经干细胞(ENSC)使用 成熟后，表达Sox10的细胞在健康肠道中失去神经生成潜力，但在特定的 损伤类型，表明某些青少年保护因子(JPF)允许Sox10+细胞 幼年肠道中产生的神经元在成年时会丢失，但在成年时会在受伤时重新引入。持续不断的 整个生命中神经元的发生表明，在青少年或成年生命中神经元的持续丢失是 由于当时活跃的ENSC的神经生成能力明显不足。与老龄化相关 伴随着肠道神经元的显著丧失和相关的慢性肠道运动障碍，表明 成人ENSC的神经发生能力不足是造成这种障碍的原因，也是制作的关键 对老年患者的长期治疗在于找到新的策略来增加或补充现有的 成人神经发生以使ENS结构和功能正常化。成体Sox10+细胞的潜在神经生成能力 可以被JPF调制，我们假设识别、招募和重新引入JPF进入老龄化 Gut将从新恢复活力的Sox10+ENSC重新启动神经发生，这一策略成立 承诺通过补充补充剂为患有慢性肠道运动障碍的老年人提供持久缓解 成体巢蛋白+肠源性神经发生不足。在这里，我们提供了重要的初步数据， 确定一些假定的外在和内在JPF，并测试它们对ENSC行为的影响 建议，我们的目标是使用下一代测序，大规模的单细胞测量，综合 跨平台分析和尖端计算工具，以确定各种假定的JPF，描述了 它们通过的调控网络，并从功能上验证它们调节神经源性的能力 利用我们新的生物学洞察力纠正衰老动物模型中的ENS结构和功能的能力。

Project Summary/Abstract Intestinal motility is regulated by the Enteric Nervous System (ENS), which resides entirely within the gut wall and comprises the largest collection of neurons and glial cells outside of the brain. Previously, we have provided evidence that post-natal development and adult maintenance of the ENS are controlled by distinct fetal-juvenile Sox10-expressing and adult Nestin-expressing Enteric Neural Stem Cells (ENSC). With maturation, the Sox10-expressing cells lose their neurogenic potential in healthy gut but regain it after specific types of injuries, suggesting that certain juvenile protective factors (JPFs) that allow for Sox10+ cells to generate neurons in juvenile gut are lost in adults, but are re-introduced upon injury in adults. The continual genesis of neurons throughout life suggests that a consistent loss of neurons during the juvenile or adult life is due to significant insufficiencies in the neurogenic capacity of ENSC active at that time. Aging is associated with significant loss of enteric neurons and associated chronic intestinal dysmotility, suggesting that an insufficiency in neurogenic capacity of adult ENSC is responsible for such disorders and that the key to crafting a long-term cure for the elderly patients rests in finding novel strategies to increase or supplement existing adult neurogenesis to normalize ENS structure and function. If latent neurogenic capacity of adult Sox10+ cells can be modulated by JPFs, we hypothesize that identifying, recruiting, and re-introducing JPFs into the aging gut would restart neurogenesis from the newly re-invigorated Sox10+ ENSC and that this strategy holds promise for providing lasting relief to elderly suffering from chronic intestinal dysmotility by supplementing insufficient adult Nestin+ derived enteric neurogenesis. Here, we provide significant preliminary data that identifies some putative extrinsic and intrinsic JPFs and test their effect on ENSC behavior and in this proposal, we aim to use next-generation sequencing, large-scale single-cell measurements, integrative cross-platform analyses, and cutting-edge computational tools to identify diverse putative JPFs, describe the regulatory networks through which they act, and functionally validate their ability to modulate neurogenic capacity using our novel biological insight to correct ENS structure and function in animal models of aging.