Mechanisms integrating hypoxia responses with proteostasis

描述（由申请人提供）：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。了解如何操纵应激反应途径可能具有重要的临床应用，可以延缓或减少许多与年龄相关的疾病。这一目标受到目前我们对基本应激反应途径的理解差距的阻碍，特别是多重应激如何在生理上相互作用。我们已经发现，特定的缺氧条件会破坏蛋白质稳态、蛋白质生产、折叠、质量控制和降解的协调，从而保持蛋白质组的完整性。我们进一步表明，禁食可以防止缺氧对蛋白质平衡的影响。amp活化激酶（AMPK）的aak-2亚基是一个保守的能量传感器，是这些效应的中心调节器。在喂养动物中，AMPK介导缺氧诱导的蛋白酶平衡破坏。然而，AMPK在禁食动物中具有相反的作用，需要aak-2来保护蛋白质静止。拟议研究的目的是揭示缺氧和AMPK激活对喂养和禁食动物的不同影响的机制。然后，我们将利用我们在缺氧和食物剥夺的情况下操纵蛋白质平衡的能力来检验蛋白质平衡途径中的缺陷驱动衰老和相关生理衰退的假设。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毒性蛋白聚集变化的介导过程。了解缺氧信号如何调节蛋白质平衡可能为这些毁灭性疾病提供新的治疗策略。此外，本研究的结果将为生物在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，并开始揭示对不同应激条件的稳态反应是如何整合的。

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.