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）：K 08奖的申请描述了一个多学科的5年培训计划，以促进拉伦贝克尔博士作为一个独立的学术医生，科学家的职业发展。该候选人是一名医学博士，2009年加入斯坦福大学胃肠病学系，现在寻求建立他的研究经验，以实现他的长期职业目标，成为一名独立的研究人员，指导神经胃肠病学和衰老的研究项目。该K 08奖项将为Becker博士提供必要的支持和保护时间，以实现以下培训目标：（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，包括掌握免疫表型分析和骨髓嵌合体的创建等技术，（3）获得学术生涯的重要技能，包括科学写作和口头陈述，以及（4）在第四年提交R 01申请。为了实现这些目标，候选人组建了一个强大的指导团队，由GI免疫学，衰老和神经胃肠病学专家组成，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他的导师和咨询委员会定期会议，教学，并出席当地和国际会议。斯坦福大学是一所世界级的机构，在免疫学、干细胞和衰老研究方面具有特别的优势，是发展候选人学术生涯的理想环境。研究衰老引起胃肠功能的生理变化，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，但肠神经系统（ENS）中神经元的丢失和变性可能起作用。拟议的研究是基于这样的发现，即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。虽然尚不清楚肠神经干细胞（ENSC）的下降是否会导致肠神经元随着衰老而丢失，但ENSC参与神经发生的发现支持了这一解释。有趣的是，Foxo 3是一种与人类长寿相关的转录因子，最近发现它在炎症性疾病中发挥作用，包括克罗恩病和风湿性关节炎。研究发现，树突状细胞（DC）中Foxo 3信号转导的缺失会增加IL-6的产生并驱动炎症。基于发现ENS微环境中Foxo 3表达随衰老下降和促炎细胞因子升高的初步数据，推测衰老由于DC中Foxo 3信号传导的减少而增加炎症，这反过来通过功能性ENSC的下降引起年龄相关的ENS紊乱。这一假设将以两种方式加以论述。首先，将检查Foxo 3在ENSC的年龄依赖性损失中的作用。具体而言，候选人将评估1）DC中的Foxo 3表达是否随着衰老而下降，2）Foxo 3缺乏是否导致ENSC和肠神经元的过早丧失，以及3）免疫细胞中的Foxo 3缺乏是否特别是导致ENS的丧失。其次，将检查炎症的年龄依赖性Foxo 3调节如何影响ENSC。具体而言，候选人将评估1）衰老是否导致ENS微环境中促炎细胞因子和免疫细胞增加，并且Foxo 3缺乏是否增强这些炎症变化，2）阻断促炎细胞因子IL-6是否将改善培养物中ENSC的存活，以及3）体内施用IL-6是否将促进ENSC的存活。 抑制神经发生。这些研究的成功完成将为年龄相关的ENS变化机制提供有价值的新见解。此外，它将为免疫调节治疗在年龄相关的胃肠道疾病中发挥作用提供原则证据。该提案将作为贝克尔博士获得GI免疫学和衰老方面额外培训的平台，这对发展神经胃肠病学研究领域至关重要。此外，这项研究将作为独立研究者为未来的研究提供基础，包括评估通过体内IL-6阻断靶向炎症是否可以逆转ENS的年龄相关变化，衰老诱导的炎症是否在人类中发挥类似作用，以及最终免疫调节疗法是否可以作为衰老相关GI疾病的治疗。