The impact of stress neurohormones on health and aging

应激神经激素对健康和衰老的影响

• 批准号: 10672430
• 负责人: Mark Alkema
• 金额: $ 38.19万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672430
• 关键词: Ablation; Acceleration; Acute; Address; Adolescent; Adrenergic Agents; Adult; Aging; Animals; Behavioral; Binding; Biology; Caenorhabditis elegans; Calcium; Cardiovascular Diseases; Cells; Communicable Diseases; Cytoprotection; Defense Mechanisms; Development; Diabetes Mellitus; Disease; Disease susceptibility; Down-Regulation; Epigenetic Process; Epinephrine; Exposure to; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Goals; Health; Hormones; Human; IGF-1 Signaling Pathway; Image; Imaging Techniques; Impaired health; Impairment; Insulin; Insulin-Like Growth Factor I; Intestinal Secretions; Intestines; Invertebrates; Life; Link; Longevity; Mammals; Modeling; Molecular; Nematoda; Nervous System; Neuroglia; Neurohormones; Neurons; Oxidative Stress; Pathway interactions; Peptides; Persons; Pharmacology; Physiology; Predisposition; Repression; Resistance; Role; Severities; Signal Transduction; Signaling Protein; Starvation; Stress; Sympathetic Nervous System; Symptoms; System; Transcend; Transgenes; Tyramine; acute stress; analog; associated symptom; biological adaptation to stress; coping; cost; early life stress; enhancing factor; environmental stressor; experience; experimental study; fighting; gut-brain axis; in vivo; insight; insulin-like peptide; mutant; negative affect; neural; neural circuit; neuromechanism; neuroregulation; novel; optogenetics; receptor; response; stress disorder; stress management; stress reduction; transcription factor

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.

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 动物和人类，反复激活战斗或飞行反应会增加疾病的敏感性 并降低寿命。这样做的理解尚未得到充分理解。在哺乳动物中，应激障碍症状是 与高水平的压力激素（如肾上腺素）相关，这些肾上腺素是由交感神经释放的 神经系统响应急性应激。但是，神经系统和 哺乳动物中的多方面压力反应使研究飞行反应如何损害健康和 加速老化一项极其艰巨的任务。我们建议在线虫中解决这个关键问题 秀丽隐杆线虫。遗传障碍性，寿命短和相对简单的神经系统使得 秀丽隐杆线虫是发现应激生理机制的特殊模型。我们最近表明 秀丽隐杆线虫飞行反应期间释放的神经压力激素对动物的影响负面影响 通过激活胰岛素途径来健康和寿命。我们发现早期幼虫阶段尤其是 对飞行响应的负面影响敏感。秀丽隐杆线虫中的飞行响应触发了 酪胺释放，肾上腺素的无脊椎动物类似物。酪胺激活肾上腺素能的受体 肠子又导致DAF-2/胰岛素/IGF-1信号传导（IIS）途径的刺激。 DAF-2/IIS途径的刺激抑制了多个细胞保护转录因子的激活 这增强了压力抗性。相反，长期的环境压力源，例如热，饥饿或 氧化应激，减少酪胺释放并抑制IIS，从而促进细胞保护的表达 基因。酪胺因此在急性飞行和长期之间提供了依赖状态的中性切换 环境压力反应。神经应激激素与胰岛素途径之间的联系提供 一个完全新颖的范式，以了解飞行响应的持续激活如何负面 影响健康并缩短寿命。我们建议结合遗传学，药理学，行为分析 以及秀丽隐杆线虫中的成像技术，以阐明飞行反应如何激活胰岛素途径和 负面影响细胞保护防御机制。提案的目的是1：确定如何 神经压力恐怖调节非神经细胞的ILP分泌以抑制细胞保护 机制； 2：确定抑制神经应激激素释放的神经回路； 3：确定 早期压力对健康和衰老的长期影响的机制。这些完成 目的将对压力神经调节的弹性机制有深刻的了解 回复。我们预计，对压力反应的神经控制的新机械洞察力 蠕虫将与哺乳动物的生理学相似。这些目标的完成无疑将 阐明了包括人类在内的动物的压力反应的神经调节的普遍机制。 因此，从这些研究中提出的发现可能最终为压力管理和 相关疾病。