The impact of stress neurohormones on health and aging

项目摘要 该项目的主要目标是阐明压力如何对健康产生负面影响并加速衰老。在 无论是动物还是人类，反复激活战斗或逃跑反应都会增加疾病的易感性。 并缩短寿命。它是如何做到这一点的，人们还不太清楚。在哺乳动物中，应激障碍症状是 与高水平的应激激素有关，如肾上腺素，它是由交感神经释放的。 神经系统对急性应激的反应。然而，神经系统的复杂性和 哺乳动物多方面的压力反应使得研究飞行反应如何损害健康， 加速衰老是一项非常困难的任务。我们建议在线虫中解决这个关键问题 秀丽隐杆线虫遗传的易驾驭性、短暂的寿命和相对简单的神经系统， C. elegans是揭示应激生理机制的特殊模型。我们最近发现， 在C. elegans飞行反应对动物的 通过激活胰岛素通路来维持健康和寿命。我们发现早期幼虫阶段 对飞行反应的负面健康影响敏感。C.优雅触发了 释放酪胺，肾上腺素的无脊椎动物类似物。酪胺激活肾上腺素样受体， 肠道，这反过来又导致刺激β 2/胰岛素/IGF-1信号传导（IIS）途径。 刺激IL-2/IIS通路抑制多种细胞保护性转录因子的激活 增强抗压力能力。相反，长期的环境压力，如热，饥饿或 氧化应激，减少酪胺释放，抑制IIS，从而促进细胞保护因子的表达。 基因.酪胺因此在急性飞行和长期飞行之间提供了一个依赖于状态的神经开关。 环境应激反应神经应激激素和胰岛素通路之间的联系提供了 这是一个全新的范例，可以理解飞行反应的持续激活是如何产生负面影响的， 影响健康缩短寿命我们建议联合收割机结合遗传学、药理学、行为分析 和成像技术在C. elegans来阐明飞行反应如何激活胰岛素途径， 负面影响细胞保护防御机制。建议的目的是1：确定如何 神经应激激素调节非神经元细胞的ILP分泌， 机制; 2：识别抑制神经应激激素释放的神经回路; 3：确定 早期生活压力对健康和衰老的长期影响的基础机制。完成这些 aims将提供对压力的神经调节的难以捉摸的机制的深入理解 反应我们预计，新的机制的见解，神经控制的压力反应，在 蠕虫与哺乳动物的生理学也有类似的关系。这些目标的实现无疑将 阐明了动物（包括人类）应激反应神经调节的普遍机制。 因此，这些研究的结果最终可能会为压力管理提供信息， 相关疾病。

Project Summary The major goal of this project is to elucidate how stress negatively impacts health and accelerates aging. In both animals and humans, repeated activation of the fight or flight response increases disease susceptibility and reduces lifespan. How it does so is not well understood. In mammals, stress disorder symptoms are associated with high levels of stress hormones such as adrenaline, which are released by the sympathetic nervous system in response to acute stress. However, the complexity of the nervous system and the multifaceted stress response in mammals makes the study of how the flight response impairs health and accelerates aging an exceedingly difficult task. We propose to address this critical question in the nematode Caenorhabditis elegans. The genetic tractability, short lifespan, and relatively simple nervous system make C. elegans an exceptional model to uncover mechanisms of stress physiology. We recently showed that neural stress hormones that are released during the C. elegans flight response negatively impact animal´s health and lifespan by activating the insulin pathway. We found that early larval stages are particularly sensitive to the negative health impacts of the flight response. The flight response in C. elegans triggers the release of tyramine, the invertebrate analog of adrenaline. Tyramine activates an adrenergic-like receptor in the intestine, which in turn leads to the stimulation of the DAF-2/Insulin/IGF-1 signaling (IIS) pathway. Stimulation of the DAF-2/IIS pathway inhibits the activation of multiple cytoprotective transcription factors that enhance stress resistance. In contrast, long-term environmental stressors, such as heat, starvation or oxidative stress, reduce tyramine release and inhibit IIS, thereby promoting the expression of cytoprotective genes. Tyramine thus provides a state-dependent neural switch between the acute flight and long-term environmental stress response. The link between neural stress hormones and the insulin pathway provides a completely novel paradigm to understand how the perpetuated activation of the flight response negatively affects health and shortens lifespan. We propose to combine genetics, pharmacology, behavioral analysis and imaging techniques in C. elegans to elucidate how the flight response activates the insulin pathway and negatively affects cytoprotective defense mechanisms. The aims of the proposal are 1: Determine how neural stress hormones modulate ILP secretion from non-neuronal cells to inhibits cytoprotective mechanisms; 2: Identify neural circuits that inhibit the release of neural stress hormones; 3: Determine the mechanisms that underlie long-lasting impacts of early-life stress on health and aging. Completion of these aims will provide a deep understanding into elusive mechanisms of neural modulation of the stress response. We anticipate that new mechanistic insights into the neural control of the stress response in the worm will be similarly relevant to mammalian physiology. The completion of these aims will undoubtedly illuminate universal mechanisms of neural modulation of the stress response in animals, including humans. Therefore, the findings emerging from these studies may ultimately inform the management of stress and associated disorders.