Transcriptional Regulation of Autophagy in Promoting Proteostasis Upon Hormetic Stress

项目摘要 细胞应激反应已经进化以适应不断变化的环境条件。衰老是 伴随着非功能性生物分子的细胞积累，包括蛋白质聚集体，和 应激反应和细胞保护机制已经成为重要的细胞机制， 预防衰老相关的功能障碍和疾病，包括神经退行性疾病。了解如何 因此，调节应激反应是朝着开发新策略迈出的重要一步， 维持细胞稳态和有机体健康。 虽然严重的压力对细胞和生物体是有害的，但温和的压力可以是有益的， 健康和寿命，一种被称为毒物兴奋效应的生物现象。这种反应是高度保守的 包括热休克反应的诱导。我最近报道说， 线虫C.温和的激素性热应激也导致自噬的诱导， 在衰老和与年龄有关的疾病中起重要作用的稳态细胞再循环过程。 因此，我观察到自噬基因是长寿的长期激素益处所必需的。 重要的是，我还发现，轻度的热应激可以改善多种蛋白质折叠疾病模型， 自噬依赖的方式。这些发现强调了毒物兴奋效应作为一种新的范式，以防止 神经退行性疾病，并发现自噬是一个重要的细胞保护机制， C.对热胁迫的有益反应优雅然而，自噬的调节机制 对兴奋性紧张性刺激反应的诱导是完全未知的。 重要的是，我的研究表明，激素介导的自噬和蛋白质稳态诱导 可能受到转录控制。为了了解毒物兴奋效应的转录机制 诱导自噬，以改善蛋白质稳态，我建议使用一个强大的组合遗传筛选和下一步 在易处理的模式生物C.优雅我会发现新的调节器， 对自噬转录的影响，并揭示了对长期 促进蛋白质稳定的激素适应。 了解自噬确保多细胞中细胞保护作用的调节机制， 细胞生物如C.秀丽线虫将是重要的操纵自噬在健康以及 自噬失调的疾病因此，这些发现可能对我们如何治疗 蛋白质聚集性疾病

PROJECT SUMMARY Cellular stress responses have evolved for the adaptation to ever-changing environmental conditions. Aging is accompanied by the cellular accumulation of non-functional biomolecules, including protein aggregates, and stress responses and cyto-protective mechanisms have emerged as important cellular mechanisms that prevent aging-related dysfunction and disease, including neurodegenerative disorders. Understanding how stress responses are regulated is therefore an important step towards developing new strategies for maintaining cellular homestasis and organismal health. While severe stress is detrimental for cells and organisms, a mild stress can be beneficial and improve health and lifespan, a biological phenomenon referred to as hormesis. This response is highly conserved amongst organisms and includes the induction of the heat-shock response. I recently reported that exposure of the nematode C. elegans to a mild hormetic heat stress also leads to the induction of autophagy, a homeostatic cellular recycling process that plays important roles in aging and age-related diseases. Consistently, I observed that autophagy genes are required for the long-term hormetic benefits on longevity. Importantly, I also discovered that a mild heat stress can improve multiple protein-folding disease models in an autophagy-dependent fashion. These findings highlight hormesis as a novel paradigm to protect against neurodegenetive diseases, and discovered autophagy to be an important cytoprotective mechanism in the beneficial response to heat stress in C. elegans. However, the regulatory mechanisms underlying autophagy induction in response to hormetic stressors are completely unknown. Importantly, my studies have indicated that hormesis-mediated induction of autophagy and proteostasis could be subject to transcriptional control. To understand the transcriptional mechanisms by which hormesis induces autophagy to improve proteostasis, I propose to use a strong combination of genetic screens and next generation seqeuencing in the tractable model organism C. elegans. I will discover novel regulators with effects on autophagy transcription and uncover the transcriptional changes important for the long-term hormetic adaptations that improve proteostasis. Understanding the regulatory mechanisms by which autophagy ensures cytoprotective effects in multi- cellular organisms like C. elegans will be important for the manipulation of autophagy in health as well as diseases with deregulated autophagy. These findings could thus have tremendous impact on how we treat protein-aggregation diseases.