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O2可用性有限的条件。这些策略允许在不景气时期生存也可以增加寿命，因为动物寿命可以通过减少O2或食物消耗来增加。了解如何操纵应激反应途径可能具有重要的临床应用，可以延迟或减少许多与年龄相关的疾病。这一目标是阻碍了目前的差距，我们的理解基本的压力反应途径，特别是如何多重压力相互作用的生理。我们已经发现，特定的缺氧条件破坏蛋白质稳态，蛋白质生产，折叠，质量控制和降解的协调，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稳态的影响。AMP激活激酶（AMPK）的aak-2亚基是一种保守的能量传感器，是这些效应的中心调节因子。在进食动物中，AMPK介导缺氧诱导的蛋白质稳态破坏。然而，AMPK在禁食动物中具有相反的作用，这需要aak-2来保护蛋白质稳态。拟议研究的目标是揭示缺氧和AMPK激活在进食和禁食动物中的不同影响的机制。然后，我们将使用我们的能力，操纵蛋白质与缺氧和食物剥夺测试的假设，即蛋白质途径的缺陷驱动衰老和相关的生理下降。这些实验的重点是揭示介导与进行性神经退行性疾病相关的毒性蛋白质聚集变化的过程。了解缺氧信号如何调节蛋白质稳态可能会为这些毁灭性疾病提供新的治疗策略。此外，这项研究的结果将提供独特的见解，生物体如何响应时，面对多种环境刺激的基本特征，并开始揭示如何整合不同的压力条件下的稳态反应。

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.