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

肠道幼年保护因子的鉴定及其在刺激成人和衰老肠神经系统神经发生中的作用

• 批准号: 10534763
• 负责人: Loyal Andrew Goff
• 金额: $ 65.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534763
• 关键词: Adolescent; Adult; Affect; Age; Aging; Animal Model; Behavior; Biological; Brain; Cell physiology; Cells; Chronic; Collection; Cues; Data; Death Rate; Dedications; Development; Diet; Disease; Elderly; Enteral; Enteric Nervous System; Functional disorder; Gene Expression Profile; Goals; Health; Injury; Intestinal Motility; Intestines; Life; Location; Maintenance; Mammals; Measurement; Molecular; Mus; Neuroglia; Neurons; Pathologic; Pathway interactions; Patients; Phase; Population; Process; Production; Proteome; Quality of life; Resolution; Rest; Resuscitation; Role; Source; Structure; Testing; Therapeutic; Time; Toxin; adult neurogenesis; age related; cell behavior; cell motility; computerized tools; fetal; improved; in vivo; injured; injury and repair; insight; mechanical force; microbial; microbiota; motility disorder; nerve stem cell; nestin protein; neurogenesis; neuron loss; next generation sequencing; normal aging; novel; novel strategies; older patient; postnatal; postnatal development; protective factors; recruit; regenerative therapy; repair function; repaired; stem cells; stressor; transcriptome; transcriptomics

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.

项目总结/摘要 肠运动是由肠神经系统（ENS），它完全驻留在肠壁调节 并且包括脑外最大的神经元和神经胶质细胞的集合。此前，我们有 提供的证据表明，出生后的发展和成人的ENS的维护是由不同的 表达Sox 10的胎儿-幼年和表达Nestin的成体肠神经干细胞（ENSC）。与 Sox 10表达细胞成熟后，在健康肠道中失去了它们的神经原性潜力，但在特定的 损伤类型，这表明某些青少年保护因子（JPF），允许Sox 10+细胞， 在幼年肠道中产生的神经元在成年人中丢失，但在成年人中受伤后重新引入。不断 神经元在整个生命过程中的发生表明，在青少年或成年生活中神经元的持续丧失， 这是因为当时ENSC的神经原性能力处于活跃状态。衰老与 肠神经元的显著损失和相关的慢性肠动力障碍，表明 成人ENSC的神经原性能力不足是导致这些疾病的原因， 老年患者的长期治疗取决于寻找新的策略来增加或补充现有的 成体神经发生使ENS结构和功能正常化。如果成体Sox 10+细胞的潜在神经原性能力 可以通过JPF调节，我们假设识别，招募，并重新引入JPF到老化中， 肠将从新恢复的Sox 10 + ENSC重新启动神经发生，并且这种策略适用于 承诺为患有慢性肠道动力障碍的长者提供持久的纾缓， 成体巢蛋白+衍生的肠神经发生不足。在这里，我们提供了重要的初步数据， 确定了一些假定的外在和内在的JPF，并测试了它们对ENSC行为的影响， 我们的目标是使用下一代测序，大规模的单细胞测量，集成 跨平台分析和尖端的计算工具，以确定各种假定的JPF，描述了 调节网络，通过它们的行为，并在功能上验证其调节神经原性的能力， 利用我们新的生物学见解，在衰老动物模型中纠正ENS结构和功能的能力。