Nutrient signaling and stem cell maintenance in aging epithelia

衰老上皮细胞的营养信号传导和干细胞维持

• 批准号: 9193600
• 负责人: Heinrich Jasper
• 金额: $ 73.27万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193600
• 关键词: Address; Age; Aging; Aging-Related Process; Animals; Basal Cell; Biological; Biological Models; Calories; Cell Aging; Cell Maintenance; Cell physiology; Chronic; Chronic Obstructive Airway Disease; Clinical Research; Collaborations; Complex; Diet; Disease; Drosophila genus; Epithelial; Epithelium; Exposure to; Food; Functional disorder; Genetic; Genetic study; Goals; Health; Homeostasis; Human; Intervention; Intestines; Knock-out; Life; Life Extension; Longevity; Maintenance; Midgut; Modeling; Molecular; Mus; Natural regeneration; Nutrient; Organism; Pathology; Pathway interactions; Pharmacology; Protocols documentation; Regulation; Repression; Role; Signal Pathway; Signal Transduction; Sirolimus; Stem cells; System; TSC1/2 gene; Testing; Therapeutic; Tissues; Trachea; Vertebrates; Wild Type Mouse; Work; age related; base; experience; fly; improved; in vivo; inhibitor/antagonist; insight; prevent; public health relevance; regenerative; response; sensor; small molecule inhibitor; stem cell differentiation; synergism

DESCRIPTION (provided by applicant): The age-related decline in regenerative capacity of many tissues constitutes a poorly understood problem that limits human healthspan. As studies in vertebrate systems point to both stem cell (SC) autonomous and non- autonomous causes for this age-related decline, analyzing SC function in an in vivo context is required, preferentially i short-lived, genetically accessible model systems. In recent years, Dr. Jasper's lab has established the fly intestine as a model to explore somatic SC aging, and to identify interventions that modulate SCs to preserve tissue homeostasis and extend lifespan. The Drosophila posterior midgut epithelium is regenerated by intestinal SCs (ISCs), is experimentally accessible, and of sufficient complexity to model the regenerative activity of similar tissues in vertebrates. Studies in the fly midgut have not only discovered mechanisms that promote the age-related regenerative decline in this tissue, but have also established that improving ISC proliferative homeostasis extends lifespan. Dr. Kennedy's lab, in turn, has performed groundbreaking work on aging and progeroid diseases for many years, with a specific recent focus on nutrient-responsive signaling pathways in the control of aging in mice. Here, Dr. Jasper and Dr. Kennedy propose to combine the strength of the fly system with genetic studies in mice to uncover evolutionarily conserved mechanisms of SC aging. Specifically, it will be tested whether the control of SC maintenance by nutrient-responsive signaling, which the applicants have characterized in the ISC lineage, is conserved in the mouse tracheal epithelial SC (Basal Cell, BC) lineage. The BC lineage has significant similarity with the fly ISC lineage, and serves as an accessible model for insight into epithelial regeneration in vertebrates that is likely to impact a major disease of aging: chronic obstructive pulmonary disease (COPD). The proposed work will address the role of TSC/Tor signaling, a conserved regulator of lifespan, on SC maintenance in flies and mice. Based on preliminary results, the applicants propose a conserved role for the negative regulator of Tor, TSC1/2, in shielding somatic SCs from dietary fluctuations, thus preserving SC identity and regenerative capacity in aging tissues. This model will be tested using genetic and pharmacological approaches to perturb the Tor pathway and to assess SC maintenance and regenerative capacity in aging animals. The study, which includes genetic work in mice and flies, as well as pharmacological interventions with new TorC1-specific inhibitors, will be performed in close collaboration between the Kennedy and Jasper labs, making the multi-PI mechanism optimal. The TSC/Tor pathway has emerged as an evolutionarily conserved nutrient sensor that influences life- and healthspan. Characterizing the biological consequences of long-term Tor repression is critical to develop specific intervention protocols that can promote tissue homeostasis and maintain regenerative capacity. The proposed studies will seek to achieve this important goal.

描述（由申请人提供）：许多组织的再生能力与年龄相关的下降构成了一个限制人类健康范围的问题。由于脊椎动物系统中的研究指出了与年龄相关的年龄下降的干细胞（SC）自主和非自主原因，因此需要在体内分析SC功能，优先是I短暂的，遗传上可访问的模型系统。近年来，贾斯珀（Jasper）博士的实验室已经建立了蝇肠作为探索体细胞衰老的模型，并确定调节SC的干预措施以保留组织稳态并延长寿命。果蝇后肠上肠上皮被肠道SC（ISC）再生，在实验上是可访问的，并且具有足够的复杂性，可以模拟脊椎动物中相似组织的再生活性。蝇中肠的研究不仅发现了促进该组织中与年龄相关的再生下降的机制，而且还确定改善ISC增殖性稳态会延长寿命。多年来，肯尼迪博士的实验室反过来曾在衰老和后代疾病方面进行了突破性的工作，最近特别关注了小鼠衰老的营养反应信号传导途径。贾斯珀（Jasper）博士和肯尼迪（Kennedy）博士在这里提议将飞行系统的强度与小鼠的遗传研究相结合，以发现SC衰老的进化保守机制。具体而言，将测试申请人在ISC谱系中表征的营养响应信号传导对SC维护的控制是否在小鼠气管上皮上皮SC（基底细胞，BC）谱系中保守。 BC谱系与Fly ISC谱系具有显着相似之处，并且是一种可访问的模型，可洞悉脊椎动物的上皮再生，这可能会影响主要的衰老：慢性阻塞性肺部疾病（COPD）。拟议的工作将解决TSC/TOR信号的作用，TSC/TOR信号是寿命的保守调节器，在苍蝇和小鼠中的SC维护中的作用。基于初步结果，申请人提出了TOR，TSC1/2的负调节剂的保守作用，它在避免饮食波动的屏蔽中屏蔽了体细胞SC，从而保留了SC的身份和衰老组织中的再生能力。该模型将使用遗传和药理方法进行测试，以扰动TOR途径并评估衰老动物的SC维持和再生能力。这项研究包括小鼠和果蝇中的遗传工作，以及与新的Torc1特异性抑制剂的药理干预措施，将在肯尼迪和Jasper Labs之间密切合​​作，使多PI机制最佳。 TSC/TOR途径已成为影响生命和健康范围的进化保守的营养传感器。表征长期TOR抑制的生物学后果对于开发特定的干预方案至关重要，这些方案可以促进组织稳态并保持再生能力。拟议的研究将寻求实现这一重要目标。