Mechanisms of Oxidative Stress and Inflammation during Prolonged Fasting and Slee

描述（由申请人提供）：北方象海豹已经进化出强大的生理机制，使它们能够适应人类或其他哺乳动物可能引起心血管和呼吸系统并发症的一些极端环境条件。例如，所有象海豹都经历了长达3个月的长期绝对食物和水的剥夺，而没有表现出任何脱水或电解质失衡的迹象。在1个月大的时候，幼崽突然断奶，开始2- 3个月的禁食，同时继续发育潜水所需的器官系统，这将在断奶后的禁食中随之而来。而在海上，海象通常会潜到500米以上的深度，在水下停留40-60分钟，然后在下一次潜水前返回水面进行2-3分钟的气体交换。此外，海象表现出慢性（80%的时间）睡眠呼吸暂停发作（11分钟），在3分钟内诱发动脉P02达到40 mmHg。独立地说，这些行为中的任何一种都可能引起许多心血管和呼吸系统并发症；然而，海象已经进化出了对抗这些行为的有害影响的机制，这在哺乳动物中是无与伦比的。由于这项倡议将支持研究，开始阐明哺乳动物进化的机制，这些机制独特地适应极端环境条件，引起人类危及生命的心血管和呼吸反应，海象提供了一个理想的模型来满足这些要求。这一建议将阐明象海豹氧化应激和炎症的细胞和系统机制，这些机制通常与长时间的食物和水剥夺以及睡眠呼吸暂停有关。我们的具体目标是：1)通过量化海象长时间禁食时氧化应激和炎症的循环和细胞标志物，阐明血管紧张素II升高对氧化应激和炎症的细胞机制的贡献；2)通过量化海象长时间禁食时氧化应激和炎症的循环和细胞标志物，阐明皮质醇升高对氧化应激和炎症的细胞机制的贡献；3)阐明自然适应海象长时间睡眠呼吸暂停诱导的缺氧诱导的细胞抗氧化和抗炎机制。由于已知该物种的肾素-血管紧张素系统（RAS）和皮质醇随禁食而改变，因此我们将重点研究RAS和糖皮质激素在禁食和睡眠呼吸暂停期间介导氧化应激和炎症的作用。这些目标的完成将为海象进化出的适应机制提供新的信息，以减少或减轻氧化应激和炎症的后果，这些后果通常与人类长期食物剥夺和睡眠呼吸暂停有关，从而努力确定新的治疗靶点。公共卫生相关性：除了慢性睡眠呼吸暂停引起的缺氧外，海象还会经历长时间的食物和水的剥夺，这两种情况都会迅速引起人类的心血管和呼吸系统并发症。然而，这些海豹必须进化出独特的强大的生理和细胞机制来对抗这些行为通常带来的潜在有害后果。这些机制在海豹的阐明可能揭示新的治疗靶点，以帮助减轻这些后果在人类。拟议的研究为发展北象海豹作为可行的生物医学模型提供了初步的步骤，以研究自然适应性的进化，以对抗氧化应激和炎症事件，这些事件通常由长时间的食物剥夺和睡眠和潜水相关的缺氧引起。

DESCRIPTION (provided by applicant): Northern elephant seals have evolved robust physiological mechanisms that have allowed them to adapt to a number of extreme environmental conditions that in humans or other mammals would evoke a number of cardiovascular and respiratory complications. For example, all elephant seals experience protracted periods of absolute food and water deprivation for up to 3 months without exhibiting any indices of dehydration or electrolyte imbalances. At 1 month of age, pups are abruptly weaned and commence a 2- 3 month long fast, all-the-while continuing to develop organ systems required for diving that will ensue following their postweaning fast. While at sea elephant seals routinely dive to depths in excess of 500 m remaining submerged for 40-60 mins followed by return to the surface for gas exchange for only 2-3 mins before the next dive. In addition, elephant seals exhibit chronic (80% of time) bouts of sleep apnea (11 min) that induce arterial P02 of 40 mmHg within 3 min. Independently, any of these behaviors could potentially evoke a number of cardiovascular and respiratory complications; however elephant seals have evolved mechanisms to counter the deleterious effects of these behaviors collectively, which is unparalleled amongst mammals. Because this initiative will support studies to begin to elucidate the mechanisms evolved in mammals uniquely adapted to extreme environmental conditions that evoke life-threatening cardiovascular and respiratory responses in humans, the elephant seal provides an ideal model to fulfill these requirements. This proposal will elucidate in elephant seals the cellular and systemic mechanisms of oxidative stress and inflammation commonly associated with prolonged food and water deprivation and sleep apnea. Our specific aims are: 1) to elucidate the contribution of elevated angiotensin II to the cellular mechanisms of oxidative stress and inflammation by quantifying circulating and cellular markers of oxidative stress and inflammation during prolonged fasting in elephant seals, 2) to elucidate the contribution of increased cortisol to the cellular mechanisms of oxidative stress and inflammation by quantifying circulating and cellular markers of oxidative stress and inflammation during prolonged fasting in elephant seals, and 3) to elucidate the cellular antioxidant and anti-inflammatory mechanisms induced during prolonged sleep apnea-induced hypoxia in naturally adapted elephant seals. Because the renin- angiotensin system (RAS) and cortisol are known to change with fasting in this species, we will focus on the contribution of RAS and glucocorticoids to mediating oxidative stress and inflammation during fasting and sleep apnea. Completion of these aims will provide novel information on the adapted mechanisms evolved by elephant seals to minimize or alleviate the consequences of oxidative stress and inflammation commonly associated with protracted food deprivation and sleep apnea in humans in an effort to identify novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Elephant seals experience prolonged periods of food and water deprivation in addition to chronic sleep apnea-induced hypoxia, both of which can rapidly evoke cardiovascular and respiratory complications in humans. However, these seals must have evolved uniquely robust physiological and cellular mechanisms to counter the potentially detrimental consequences commonly associated with these behaviors. Elucidation of these mechanisms in seals may reveal novel therapeutic targets to help alleviate these consequences in humans. The proposed studies provide the initial steps towards developing the Northern elephant seal as a viable biomedical model to study the natural adaptations evolved to counter oxidative stress and inflammatory events commonly induced by prolonged food deprivation and, sleep- and diving-associated hypoxia.