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）：这份 K08 奖项申请描述了一项为期 5 年的多学科培训计划，以促进 Laren Becker 博士作为独立学术医师科学家的职业发展。该候选人是医学博士、博士，于 2009 年加入斯坦福大学胃肠病学系，现在寻求利用自己的研究经验来实现自己的长期职业目标，即成为一名独立研究者，指导神经胃肠病学和衰老方面的研究项目。该 K08 奖项将为 Becker 博士提供完成以下培训目标所需的支持和受保护的时间：(1) 成为神经胃肠病学、免疫学和衰老方面的专家，(2) 精通免疫学研究，包括掌握以下技术免疫表型分型和骨髓嵌合体的创建，(3) 获得对学术生涯重要的技能，包括科学写作和口头报告，以及 (4) 在第 4 年提交 R01 申请。为了实现这些目标，候选人组建了一支由胃肠道免疫学、衰老和神经胃肠病学专家组成的强大指导团队，他们都成功地指导了年轻科学家。贝克尔博士的职业发展计划包括与导师和咨询委员会定期举行会议、讲授以及出席本地和国际会议。斯坦福大学是一所世界一流的学府，在免疫学、干细胞和衰老研究方面具有独特的实力，是候选人发展学术生涯的理想环境。研究 衰老会导致胃肠道功能发生生理变化，从而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了一定作用。拟议的研究基于以下发现：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所致。虽然尚不清楚肠道神经干细胞 (ENSC) 的减少是否会导致肠道神经元随着衰老而丧失，但 ENSC 参与神经发生的发现支持了这一解释。有趣的是，Foxo3（一种与人类长寿相关的转录因子）最近被发现在包括克罗恩病和类风湿性关节炎在内的炎症性疾病中发挥作用。研究发现，树突状细胞 (DC) 中 Foxo3 信号传导的缺失会增加 IL-6 的产生并引发炎症。初步数据发现，随着年龄的增长，ENS 微环境中 Foxo3 表达下降，促炎细胞因子增加，推测衰老会由于 DC 中 Foxo3 信号传导减少而增加炎症，进而通过功能性 ENSC 的下降。这一假设将通过两种方式得到解决。首先，将检查 Foxo3 在 ENSC 年龄依赖性丧失中的作用。具体来说，考生将评估 1) DC 中的 Foxo3 表达是否会随着衰老而下降，2) Foxo3 缺乏会导致 ENSC 和肠神经元过早丧失，以及 3) 免疫细胞中的 Foxo3 缺乏尤其会导致 ENS 丧失。其次，将检查年龄依赖性 Foxo3 炎症调节如何影响 ENSC。具体来说，考生将评估 1) 衰老是否会导致 ENS 微环境中促炎细胞因子和免疫细胞增加，而 Foxo3 缺乏会加剧这些炎症变化，2) 阻断促炎细胞因子 IL-6 将提高培养物中 ENSC 的存活率，以及 3) 给药IL-6 体内的 抑制神经发生。成功完成拟议的研究将为 ENS 与年龄相关的变化机制提供有价值的新见解。此外，它将提供免疫调节疗法在与年龄相关的胃肠道疾病中发挥作用的原理证据。该提案将为贝克尔博士提供一个平台，让他获得胃肠道免疫学和衰老方面的额外培训，这对于发展神经胃肠病学的研究领域至关重要。此外，这项研究将为未来作为独立研究者的研究奠定基础，包括评估通过体内阻断 IL-6 靶向炎症是否可以逆转 ENS 与年龄相关的变化，衰老引起的炎症是否在人类中发挥类似的作用，最终免疫调节疗法是否可以作为与衰老相关的胃肠道疾病的治疗方法。