Age induced enteric neural stem cell loss through Foxo3 dependent inflammation

年龄通过 Foxo3 依赖性炎症诱导肠神经干细胞损失

• 批准号: 8804878
• 负责人: Laren Becker
• 金额: $ 15.39万
• 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 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804878
• 关键词: Address; Advisory Committees; Affect; Age; Age-associated memory impairment; Aging; Aging-Related Process; Anorexia; Apoptosis; Award; Benzalkonium Chloride; Biological Neural Networks; Bone Marrow; Cell Aging; Cells; Chimera organism; Constipation; Controlled Study; Crohn' s disease; Data; Dendritic Cells; Development Plans; Disease; Doctor of Philosophy; Elderly; Enteral; Enteric Nervous System; Environment; Etiology; Family; Fecal Incontinence; Flow Cytometry; Foundations; Future; Gastroenterology; Gastrointestinal Diseases; Goals; Hematopoietic; Human; Immune; Immunology; Immunophenotyping; Impaired cognition; In Vitro; Incubated; Inflammation; Inflammatory; Injury; Institution; Interleukin-6; International; Intestines; Knockout Mice; Lead; Link; Longevity; Mentors; Mus; Nerve Degeneration; Nervous System Trauma; Neuraxis; Neurons; Oral; Physicians; Physiological; Play; Population; Production; Quality of life; Recombinants; Reporting; Research; Research Personnel; Rheumatoid Arthritis; Role; Scientist; Signal Transduction; Societies; Stem cells; Tamoxifen; Techniques; Testing; Time; Training; Training Programs; Writing; age related; base; career; career development; cell age; cytokine; experience; functional loss; gastrointestinal; gastrointestinal function; improved; in vivo; inhibitor/antagonist; insight; meetings; member; multidisciplinary; nerve stem cell; neurogenesis; neuron loss; neutralizing antibody; premature; prevent; programs; public health relevance; skills; small molecule; transcription factor

DESCRIPTION (provided by applicant): This application for a K08 award describes a multidisciplinary 5-year training program to facilitate Dr. Laren Becker's career development as an independent academic physician-scientist. The candidate is a MD, PhD who joined the Gastroenterology Department at Stanford in 2009 and now seeks to build on his research experience to attain his long-term career goal of becoming an independent investigator, directing a research program in neurogastroenterology and aging. This K08 award will provide Dr. Becker with the support and protected time necessary to accomplish the following training objectives: (1) to become an expert in neurogastroenterology, immunology and aging, (2) to become proficient in immunology research including mastering techniques such as immunophenotyping and creation of bone marrow chimeras, (3) to acquire skills important for an academic career including scientific writing and oral presentation, and (4) to submit an R01 application during year 4. To achieve these goals, the candidate has assembled a strong mentoring team of experts in GI immunology, aging and neurogastroenterology-all of whom have successfully mentored young scientists. Dr. Becker's career development plan includes regular meetings with his mentors and advisory committee, didactics, and attendance at local and international meetings. Stanford, a world-class institution with particular strength in immunology, stem cell and aging research, is the ideal environment for developing the candidate's academic career. Research 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 factors 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 dendritic cells (DCs) 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 DCs 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 loss of ENSCs will be examined. Specifically, the candidate will assess whether 1) Foxo3 expression in DCs declines with aging, 2) Foxo3 deficiency leads to premature loss of ENSCs and enteric neurons, and 3) Foxo3 deficiency in immune cells in particular is responsible for loss in the ENS. Second, how age-dependent Foxo3 modulation of inflammation impacts ENSCs will be examined. Specifically, the candidate will evaluate whether 1) aging causes increased proinflammatory cytokines and immune cells in the ENS microenvironment and Foxo3 deficiency augments these inflammatory changes, 2) blocking the proinflammatory cytokine IL-6 will improve survival of ENSCs in culture, and 3) administration of IL-6 in vivo will inhibit neurogenesis. Successful completion of the proposed sudies will offer valuable new insights regarding the mechanism of age- related changes of the ENS. Additionally, it will provide proof of principle that immunomodulatory therapies have a role in age-associated gastrointestinal disorders. This proposal will serve as a platform for Dr. Becker to acquire additional training in GI immunology and aging, crucial to developing a research niche in neurogastroenterology. Additionally, this research will provide the foundation for future studies as an independent investigator including evaluating whether targeting inflammation via blockade of IL-6 in vivo can reverse age-related changes to the ENS, whether aging-induced inflammation plays a similar role in humans, and ultimately whether immunomodulatory therapies may serve as therapy for aging associated GI disorders.

描述（由申请人提供）：该申请申请颁奖典礼描述了一项多学科的5年培训计划，以促进Laren Becker博士作为独立的学术医师科学家的职业发展。候选人是医学博士，博士学位，他于2009年加入了斯坦福大学的胃肠病学系，现在试图以他的研究经验为基础，以实现他成为独立研究人员的长期职业目标，指导神经胃肠病学和衰老的研究计划。 This K08 award will provide Dr. Becker with the support and protected time necessary to accomplish the following training objectives: (1) to become an expert in neurogastroenterology, immunology and aging, (2) to become proficient in immunology research including mastering techniques such as immunophenotyping and creation of bone marrow chimeras, (3) to acquire skills important for an academic career including scientific writing and oral presentation, and （4）在第4年提交R01申请。为了实现这些目标，候选人组建了一个强大的胃肠道免疫学专家团队，衰老和神经胃肠病学专家 - 他们成功地指导了年轻的科学家。贝克尔博士的职业发展计划包括与他的导师和咨询委员会的定期会议，教义，以及参加当地和国际会议。斯坦福大学是一家世界一流的机构，在免疫学，干细胞和衰老研究方面具有特殊优势，是发展候选人学术生涯的理想环境。研究衰老会导致胃肠道肠功能的生理变化，从而导致许多与年龄有关的疾病。这些疾病的病因可能是多因素的，但是肠神经系统（ENS）中神经元的丧失和变性可能起作用。拟议的研究基于以下发现：与年龄相关的认知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。尽管未知肠神经干细胞（ENSC）的下降是否导致肠道神经元的衰老丧失，但发现ENSC参与神经发生的发现支持了这种解释。有趣的是，最近发现与人类长寿有关的转录因子在包括克罗恩病和类风湿关节炎在内的炎症性疾病中起作用。发现树突状细胞（DC）中FOXO3信号传导的丧失会增加IL-6产生并驱动炎症。基于初步数据，既发现FOXO3表达的下降又是随着衰老衰老的ENS微环境中促炎细胞因子的增加，因此人们认为，由于DC的降低，衰老会增加FOXO3信号引起的炎症，而DC中的FOXO3信号降低，这反过来导致年龄因功能性ENSC的下降而导致年龄相关的导致炎症。该假设将通过两种方式解决。首先，将检查FOXO3在依赖年龄的ENSC损失中的作用。具体而言，候选人将评估1）DC中FOXO3的表达是否随老化而下降，2）FOXO3缺乏导致ENSC和肠神经元的过早损失，以及3）免疫细胞中FOXO3缺乏症，尤其是ENS中的损失。其次，将如何检查炎症影响年龄依赖的FOXO3调节ENSC。具体而言，候选人将评估1）衰老是否导致ENS微环境中的促炎细胞因子和免疫细胞增加，而FOXO3缺乏症增加了这些炎症变化，2）阻止促炎细胞因子IL-6会改善ENSC在文化中的ENSC的存活率，以及IL-6 In Vivo的IL-6）给药。 抑制神经发生。成功完成拟议的肥皂水将提供有关ENS与年龄相关变化机制的宝贵新见解。此外，它将提供原理证明免疫调节疗法在与年龄相关的胃肠道疾病中起作用。该提案将成为贝克尔博士获得GI免疫学和衰老的其他培训的平台，这对于在神经胃肠病学上开发研究层至关重要。此外，这项研究将为未来作为独立研究者的研究为基础提供基础，包括评估通过封锁IL-6在体内阻断炎症是否可以逆转与年龄相关的ENS的变化（衰老诱发的炎症在人类中的相似作用）是否在人类中起相似的作用，以及最终是否可以作为与衰老相关的gi差异的治疗疗法。