Mechanisms of Oxidative Stress and Inflammation during Prolonged Fasting and Slee

描述(申请人提供)：北象海豹进化出了强大的生理机制，使它们能够适应一些极端的环境条件，在人类或其他哺乳动物身上会引起一些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缺乏，没有表现出任何脱水或电解质失衡的指标。在1个月大的时候，幼崽突然断奶，并开始了长达2-3个月的禁食，同时继续发育潜水所需的器官系统，这将在它们断奶后随之而来。而在海上，象海豹通常会潜到超过500米的深度，在水下停留40-60分钟，然后在下一次潜水之前返回水面进行气体交换只有2-3分钟。此外，象海豹表现出慢性(80%的时间)睡眠呼吸暂停(11分钟)，在3分钟内导致动脉血氧分压(P02)达到40毫米汞柱。独立地说，这些行为中的任何一种都可能引起一些心血管和呼吸系统并发症；然而，象海豹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。由于这一倡议将支持研究开始阐明哺乳动物独特地适应极端环境条件的进化机制，这些极端环境条件会在人类引发危及生命的心血管和呼吸反应，因此象海豹提供了一个满足这些要求的理想模型。这项提议将阐明海象体内氧化应激和炎症的细胞和系统机制，这些机制通常与长期缺乏食物和水以及睡眠呼吸暂停有关。我们的具体目标是：1)通过量化长时间禁食期间象海豹体内氧化应激和炎症的循环和细胞标记物，阐明血管紧张素II的升高在氧化应激和炎症的细胞机制中的作用；2)通过定量长时间禁食期间象海豹体内氧化应激和炎症的循环和细胞标记物，阐明皮质醇增加在氧化应激和炎症的细胞机制中的作用；以及3)阐明在自然适应的睡眠呼吸暂停诱导的低氧条件下，细胞抗氧化和抗炎机制。由于已知肾素-血管紧张素系统(RAS)和皮质醇在该物种中随禁食而改变，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在介导氧化应激和炎症中的作用。完成这些目标将提供关于象海豹进化的适应机制的新信息，以最大限度地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缺乏食物和睡眠呼吸暂停有关，以努力确定新的治疗靶点。与公共卫生相关：除了慢性睡眠呼吸暂停导致的低氧外，象海豹还会经历长时间的食物和水缺乏，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，以对抗通常与这些行为相关的潜在有害后果。阐明海豹体内的这些机制可能会揭示新的治疗靶点，以帮助缓解人类的这些后果。拟议的研究为将北象海豹发展为一个可行的生物医学模型提供了初步步骤，以研究为对抗氧化应激和炎症事件而进化的自然适应，这些事件通常是由长期食物剥夺以及睡眠和潜水相关的低氧引起的。

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.