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，使其能够适应许多极端环境条件，这些条件在人类或其他哺乳动物中会引起许多心血管和呼吸系统并发症。例如，所有象海豹都经历了长达3个月的绝对食物和水匮乏，而没有表现出任何脱水或电解质失衡的指数。在1个月大时，幼犬突然断奶，开始2- 3个月的禁食，同时继续发育潜水所需的器官系统，这将在断奶后禁食。而在海上，象海豹通常会潜入500米以上的深度，在水下呆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），诱导动脉P02的40毫米汞柱在3分钟内。独立地，这些行为中的任何一个都可能潜在地引起一些心血管和呼吸系统并发症;然而，海象已经进化出机制来共同对抗这些行为的有害影响，这在哺乳动物中是无与伦比的。由于这一举措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于引起人类危及生命的心血管和呼吸反应的极端环境条件，因此海象提供了一个理想的模型来满足这些要求。这项建议将阐明在海象的细胞和全身机制的氧化应激和炎症通常与长期的食物和水的剥夺和睡眠呼吸暂停。我们的具体目标是：1）通过定量海象在长时间禁食期间的氧化应激和炎症的循环和细胞标志物，阐明升高的血管紧张素II对氧化应激和炎症的细胞机制的贡献，（二）为了阐明增加的皮质醇对氧化应激和炎症的细胞机制的贡献，通过定量在长时间内氧化应激和炎症的循环和细胞标志物，禁食的海象，和3）阐明细胞抗氧化和抗炎机制诱导的长期睡眠呼吸暂停诱导缺氧的自然适应海象。由于已知该物种的肾素-血管紧张素系统（RAS）和皮质醇随禁食而变化，因此我们将重点关注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。这些目标的完成将提供新的信息，适应机制演变的海象，以尽量减少或减轻后果的氧化应激和炎症通常与长期的食物匮乏和睡眠呼吸暂停在人类中，努力确定新的治疗目标。公共卫生相关性：象海豹经历长时间的食物和水剥夺，以及慢性睡眠呼吸暂停引起的缺氧，这两种情况都能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，以对抗通常与这些行为相关的潜在有害后果。阐明海豹的这些机制可能会揭示新的治疗靶点，以帮助减轻人类的这些后果。拟议的研究提供了初步的步骤，发展北方象海豹作为一个可行的生物医学模型，研究自然的适应性演变，以对抗氧化应激和炎症事件通常引起的长期食物匮乏，睡眠和潜水相关的缺氧。

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.