Nutrient signaling and stem cell maintenance in aging epithelia

描述（由申请人提供）：许多组织与年龄相关的再生能力下降构成了一个限制人类健康寿命的鲜为人知的问题。由于脊椎动物系统的研究指出了干细胞（SC）自主和非自主导致这种与年龄相关的衰退，因此需要在体内环境中分析SC功能，优先是短期的，遗传上可接近的模型系统。近年来，Jasper博士的实验室建立了果蝇肠道作为研究体细胞SC老化的模型，并确定了调节SC以保持组织稳态和延长寿命的干预措施。果蝇后中肠上皮是由肠道SCs （ISCs）再生的，在实验上是可获得的，并且具有足够的复杂性来模拟脊椎动物类似组织的再生活性。对苍蝇中肠的研究不仅发现了促进该组织与年龄相关的再生衰退的机制，而且还确定了改善ISC增殖内稳态可以延长寿命。反过来，肯尼迪博士的实验室多年来在衰老和早老年性疾病方面进行了开创性的工作，最近特别关注控制小鼠衰老的营养反应信号通路。在这里，Jasper博士和Kennedy博士建议将果蝇系统的力量与小鼠的遗传研究结合起来，以揭示SC衰老的进化保守机制。具体来说，将测试是否通过营养反应信号控制SC维持，申请人在ISC谱系中表征，在小鼠气管上皮SC（基底细胞，BC）谱系中是保守的。BC谱系与苍蝇ISC谱系具有显著的相似性，并且可以作为一种可访问的模型来深入了解脊椎动物上皮再生，这可能影响一种主要的衰老疾病：慢性阻塞性肺疾病（COPD）。这项工作将解决TSC/Tor信号在果蝇和小鼠SC维持中的作用，TSC/Tor信号是一种保守的寿命调节因子。基于初步结果，申请人提出了Tor的负调节因子TSC1/2在保护体细胞SCs免受饮食波动方面的保守作用，从而在衰老组织中保持SC的特性和再生能力。该模型将使用遗传和药理学方法进行测试，以干扰Tor通路，并评估衰老动物的SC维持和再生能力。这项研究将在Kennedy和Jasper实验室的密切合作下进行，包括小鼠和果蝇的遗传工作，以及新的torc1特异性抑制剂的药理学干预，使多pi机制达到最佳。TSC/Tor通路已成为一种进化上保守的营养传感器，影响生命和健康寿命。表征长期Tor抑制的生物学后果对于制定能够促进组织稳态和维持再生能力的特定干预方案至关重要。拟议的研究将力求实现这一重要目标。

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.