Effect of aging on enteric neural stem cells is dependent on the PI3K/Akt pathway

衰老对肠神经干细胞的影响取决于 PI3K/Akt 通路

• 批准号: 8719908
• 负责人: Laren Becker
• 金额: $ 7.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719908
• 关键词: Accounting; Address; Adult; Affect; Age; Aging; Aging-Related Process; Animals; Anorexia; Anus; Apoptosis; Biological Neural Networks; Caloric Restriction; Cell Aging; Cell physiology; Cells; Cognitive; Colon; Constipation; Data; Disease; Elderly; Enteral; Enteric Nervous System; Environment; Equilibrium; Esophagus; Etiology; Fecal Incontinence; Flow Cytometry; Foundations; Future; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Physiology; Goals; Health; Health Care Costs; Human; Impaired cognition; In Vitro; Institution; Intestines; Knowledge; Lead; Mediating; Molecular Target; Motor; Motor Neurons; Mus; Muscle; Myenteric Plexus; Myofibroblast; Nervous system structure; Neuraxis; Neuritis; Neuroglia; Neurons; Nitrergic Neurons; Nitrogen; Oxidative Stress; Oxygen; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Quality of life; Relative (related person); Research; Research Personnel; Resources; Rodent; Role; Signal Pathway; Societies; Stem cells; Stomach; Testing; Transplantation; Vitamin A; Work; age effect; age related; aged; base; career; cell age; cell motility; cholinergic; cholinergic neuron; excitatory neuron; experience; functional loss; gastrointestinal; gastrointestinal function; health care quality; improved; in vivo; inhibitor/antagonist; inhibitory neuron; nerve stem cell; neuron loss; neuroregulation; prevent; research study; senescence; skills; Accounting; Address; Adult; Affect; Age; Aging; Aging-Related Process; Animals; Anorexia; Anus; Apoptosis; Biological Neural Networks; Caloric Restriction; Cell Aging; Cell physiology; Cells; Cognitive; Colon; Constipation; Data; Disease; Elderly; Enteral; Enteric Nervous System; Environment; Equilibrium; Esophagus; Etiology; Fecal Incontinence; Flow Cytometry; Foundations; Future; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Physiology; Goals; Health; Health Care Costs; Human; Impaired cognition; In Vitro; Institution; Intestines; Knowledge; Lead; Mediating; Molecular Target; Motor; Motor Neurons; Mus; Muscle; Myenteric Plexus; Myofibroblast; Nervous system structure; Neuraxis; Neuritis; Neuroglia; Neurons; Nitrergic Neurons; Nitrogen; Oxidative Stress; Oxygen; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Quality of life; Relative (related person); Research; Research Personnel; Resources; Rodent; Role; Signal Pathway; Societies; Stem cells; Stomach; Testing; Transplantation; Vitamin A; Work; age effect; age related; aged; base; career; cell age; cell motility; cholinergic; cholinergic neuron; excitatory neuron; experience; functional loss; gastrointestinal; gastrointestinal function; health care quality; improved; in vivo; inhibitor/antagonist; inhibitory neuron; nerve stem cell; neuron loss; neuroregulation; prevent; research study; senescence; skills

DESCRIPTION (provided by applicant): Aging causes physiologic changes in gastrointestinal intestinal function that contribute to many age-related disorders. These disorders cause a significant burden both in healthcare costs and quality of life. A shift in the ratio of motor neurons favoring inhibitory (nitrergic) neurons over excitatory (cholinergic) neurons has been observed in the ENS with aging and is thought to play an important role in these disorders. While many have speculated that 'wear and tear' resulting from oxidative stress is the cause for this disturbance, the mechanism(s) underlying the effects of aging on the ENS are poorly understood. Aging is increasingly viewed as a highly regulated process. In the central nervous system (CNS), there is evidence that loss of functional neural stem cells contributes to the aging process and cognitive decline. Similar decline in stem cell function may also be contributing to age-related changes in the ENS. The goal of the proposed research is to study the effect of aging on a population of neural stem cells in the ENS, termed enteric neural stem cells (ENSCs). Recent work by the candidate suggests that ENSCs from old mice differentiate into cells that express higher levels of nNOS, a marker of nitrergic neurons, than those from young mice and that this difference may be due to higher basal Akt activity found in ENS from old mice. The candidate hypothesizes that age-related disturbances in the ENS are due to alterations in ENSC function mediated by the PI3K/Akt/FOXO pathway. The candidate plans to address this hypothesis in two ways. First, the candidate will delineate intrinsic differences in ENSCs isolated by flow cytometry from old and young mice. Specifically, the candidate will perform experiments to evaluate for differences with regards to proliferation, apoptosis, senescence, and differentiation using both in vitro and in vivo (transplantation) approaches. Second, the candidate will investigate the role of the PI3K/Akt/FOXO3 signaling pathway in the aging process in ENSCs. Specifically, the candidate will assess the basal activity of the PI3K/Akt/FOXO3 pathway in old and young ENSCs and evaluate how modulating this pathway through stimulation and inhibition affects their phenotypes. These studies will enhance our understanding of aging in the ENS and lay the foundation for future research including: 1) determining whether caloric-restriction reverses age-related changes to ENSC function, 2) evaluating whether similar age-related changes occur in human ENSCs, and 3) elucidating molecular targets that will reverse the effect of aging on ENSCs. The candidate believes that Stanford, a world-class institution with particular strength in stem cell and aging research, is th ideal environment for developing his academic career. With Dr. Anne Brunet as his senior collaborator, the abundant resources available at Stanford, and a wide range of didactics to broaden his scientific knowledge and technical skills, the candidate is uniquely placed to pursue his goal of becoming an independent investigator.

描述（由申请人提供）：衰老会导致胃肠道肠功能的生理变化，导致许多与年龄有关的疾病。这些疾病在医疗保健成本和生活质量方面造成了重大负担。在ENS中，人们观察到了有利于抑制性（硝化）神经元比兴奋性（胆碱能）神经元的运动神经元之比的变化，并且在ENS衰老的衰老中观察到，并且被认为在这些疾病中起着重要作用。尽管许多人推测，氧化应激引起的“磨损”是这种干扰的原因，但对衰老对ENS影响的机制的理解很差。越来越多地将衰老视为高度调节的过程。在中枢神经系统（CNS）中，有证据表明功能性神经干细胞的丧失有助于衰老过程和认知能力下降。干细胞功能的类似下降也可能导致ENS与年龄相关的变化。拟议研究的目的是研究衰老对ENS，称为肠神经干细胞（ENSC）中神经干细胞群的影响。候选人最近的工作表明，来自旧小鼠的ENSC分化为表达nNO水平更高的细胞，即硝化神经元的标记，比幼鼠的细胞分化，并且这种差异可能是由于旧小鼠中ENS中发现的基础Akt活性较高。候选人假设ENS中与年龄相关的干扰是由于PI3K/AKT/FOXO途径介导的ENSC功能的改变。候选人计划通过两种方式解决这一假设。首先，候选人将描述由老鼠和小鼠流式细胞仪分离的ENSC中的内在差异。具体而言，候选人将使用体外和体内（移植）方法进行实验，以评估有关增殖，凋亡，衰老和分化的差异。其次，候选人将研究PI3K/AKT/FOXO3信号通路在ENSC的衰老过程中的作用。具体而言，候选人将评估老式和年轻的ENSC中PI3K/AKT/FOXO3途径的基础活性，并评估通过刺激和抑制作用如何调节这一途径的方式会影响其表型。这些研究将增强我们对ENS中的衰老的理解，并为未来的研究奠定基础，包括：1）确定卡路里限制是否会逆转与年龄相关的ENSC功能的变化，2）评估人类ENSC中是否发生了类似的年龄相关变化，以及3）阐明分子靶标会逆转衰老对ENSC的影响。候选人认为，斯坦福大学是一个在干细胞和衰老研究中具有特殊优势的世界一流机构，是发展他的学术生涯的理想环境。与安妮·布鲁内特（Anne Brunet）博士担任高级合作者，斯坦福大学（Stanford）可获得的丰富资源，以及广泛的教学法，以扩大他的科学知识和技术技能，候选人是独特的，以实现成为独立研究员的目标。