Mechanisms integrating hypoxia responses with proteostasis

描述(申请人提供)：细胞和生物体具有复杂的应激反应，以适应食物或氧气供应有限的条件。这些允许在贫瘠时期生存的策略也可以延长寿命，因为动物的寿命可以通过减少氧气或食物消耗来延长。了解如何操纵压力反应通路可能会对延缓或减少一系列与年龄相关的疾病具有重要的临床应用。这一目标受到目前我们对基本应激反应途径的理解上的差距的阻碍，特别是多种应激如何在生理上相互作用。我们已经发现，特定的低氧条件会破坏蛋白质平衡，蛋白质生产、折叠、质量控制和降解的协调，以保持蛋白质组的完整性。我们进一步证明，禁食可以防止低氧对蛋白平衡的影响。AMP激活激酶(AMPK)的AAK-2亚基是一种保守的能量感受器，是这些效应的中心调节因子。在喂养的动物中，AMPK介导了低氧诱导的蛋白稳态的破坏。然而，AMPK在禁食动物中具有相反的作用，需要AAK-2来保护蛋白平衡。这项拟议的研究的目的是揭示低氧和AMPK激活在喂食和禁食动物中的不同影响的机制。然后，我们将利用我们在缺氧和食物缺乏的情况下操纵蛋白质平衡的能力来测试蛋白质平衡途径缺陷导致衰老和相关的生理衰退的假设。这些实验的一个重点是揭示与进行性神经退行性疾病相关的有毒蛋白质聚集变化的中介过程。了解低氧信号如何调节蛋白平衡，可能会为这些毁灭性疾病提供新的治疗策略。此外，这项研究的结果将为生物体面对多种环境刺激时如何反应的基本特征提供独特的见解，并开始揭示不同应激条件下的动态平衡反应是如何整合的。

DESCRIPTION (provided by applicant): Cells and organisms have sophisticated stress responses to adapt to conditions where the availability of food or O2 is limited. These strategies that allow for survival in lean times can also increase lifespan, as animal lifespan can be increased by reducing either O2 or food consumption. Understanding how to manipulate stress response pathways could have important clinical applications to delay or reduce a host of age-associated conditions. This goal is hampered by current gaps in our understanding of fundamental stress response pathways, especially how multiple stresses interact physiologically. We have discovered that specific hypoxic conditions disrupt proteostasis, the coordination of protein production, folding, quality control, and degradation that preserves the integrity of the proteome. We further show that fasting can protect against the effects of hypoxia on proteostasis. The aak-2 subunit of AMP-activated kinase (AMPK), a conserved energy sensor, is a central regulator of these effects. In fed animals, AMPK mediates the hypoxia-induced disruption of proteostasis. However, AMPK has the opposite role in fasted animals, which require aak-2 is required to protect proteostasis. The goal of the proposed research is to reveal mechanisms that underlie the different effects of hypoxia, and AMPK activation, in fed and fasted animals. We will then use our ability to manipulate proteostasis with hypoxia and food deprivation to test the hypothesis that defects in proteostasis pathways drive aging and the associated physiological decline. A focus of these experiments is on revealing processes that mediate changes in the aggregation of toxic proteins that are associated with progressive neurodegenerative diseases. Understanding how hypoxia signaling can modulate proteostasis may suggest new therapeutic strategies for these devastating diseases. Moreover, the results of this research will provide unique insight into fundamental features of how organisms respond when faced with multiple environmental stimuli, and begin to reveal how homeostatic responses to different stress conditions are integrated.