Elucidating the role of the Integrated Stress Response pathway in tissue homeostasis

项目摘要 整合应激反应通路在组织动态平衡中的作用 后生动物已经进化了压力响应路径来对抗内部和外部应激源(例如， 营养缺乏、环境条件变化、有毒侮辱)。综合应激 反应(ISR)是这样一种进化保守的途径，它介导对细胞的适应 压力。自从在酵母中发现ISR信号以来，人们一直致力于研究ISR信号的作用 在调节细胞对外源压力的反应中。在高等生物中，许多特化细胞 类型已经进化到依赖ISR来维持内稳态：值得注意的例子包括 代谢活跃的细胞，如肝细胞和脂肪细胞，高度分泌的细胞，如胰岛 胰腺细胞，以及具有高蛋白周转率的神经元，如光感受器。我们目前的情况 对ISR信号在维持组织动态平衡中的理解主要来自表型 在功能丧失突变体中的观察，但对潜在的分子和细胞知之甚少 这种调节的生物学。这项提议试图获得对精确的分子和细胞的新见解 ISR信号在维持组织内稳中的生物学机制。我们将使用 果蝇脂肪组织和卵巢作为发现平台，由于遗传和分子的广度 可用于操纵这些组织的生物工具。 ISR信号的不同分支最终形成高度保守的转录因子， ATF4.我们最近描述了果蝇ATF4在卵子发生调控中的作用。我们的预赛 数据显示，虽然一些卵子发生缺陷(例如，卵母细胞成熟)是由 卵巢对ATF4的自主需求，其他几种(例如，卵黄蛋白积累，卵子 产卵)是由卵巢周围脂肪组织中的ATF4非自主地介导的组织。基座 根据这些数据，我们测试了ISR信号作为脂肪组织代谢传感器的作用，它通知外周 组织的功能是非自主的。利用我们在分子和细胞生物学方面的广泛背景 用强大的果蝇遗传工具技术，我们将追求三个项目，以确立其作用 ISR信号1)调节脂肪组织中的类固醇激素信号，2)脂肪组织介导的 神经调节，以及3)卵巢中的mRNA翻译调控。获得分子 了解ISR在组织动态平衡中的作用将从根本上指导我们的方法 在实验和治疗方面改善组织功能。这项研究的进展也将 具有广泛的病理生物学意义，因为ISR失调与不断增加的 疾病的数量，从糖尿病到神经变性和癌症。

PROJECT ABSTRACT Elucidating the role of the Integrated Stress Response pathway in tissue homeostasis Metazoa have evolved stress response pathways to combat internal and external stressors (e.g., nutrient deprivation, changes in environmental conditions, toxic insults). The Integrated Stress Response (ISR) is one such evolutionarily conserved pathway that mediates adaptation to cellular stress. Since its discovery in yeast, much effort has been dedicated to studying the role of ISR signaling in mediating the cellular response to exogenous stress. In higher organisms, many specialized cell types have evolved to rely on the ISR to maintain homeostasis: notable examples of this include metabolically active cells such as hepatocytes and adipocytes, highly secretory cells such as b-islet cells of the pancreas, and neurons with high protein turnover such as photoreceptors. Our current understanding of ISR signaling in maintaining tissue homeostasis largely comes from phenotypic observations in loss-of-function mutants, yet little is known about the underlying molecular and cell biology of such regulation. This proposal seeks to gain new insights into the precise molecular and cell biological mechanisms governed by ISR signaling in maintaining tissue homeostasis. We will use the Drosophila fat tissue and ovary as a discovery platform, owing to the breadth of genetic and molecular biology tools available for manipulation of these tissues. The different branches of ISR signaling culminate in the highly conserved transcription factor, ATF4. We recently described a role for Drosophila ATF4 in the regulation of oogenesis. Our preliminary data revealed that while some of the oogenesis defects (e.g., oocyte maturation) arise from autonomous requirement for Atf4 in the ovary, several others (e.g., yolk protein accumulation, egg laying) are mediated tissue non-autonomously by Atf4 in the fat tissues surrounding the ovary. Based on these data, we test a role for ISR signaling as a fat tissue metabolic sensor, which informs peripheral tissue function non-autonomously. Leveraging our extensive background in molecular and cell biology techniques with powerful Drosophila genetic tools, we will pursue three projects to establish the role for ISR signaling 1) in regulating steroid hormone signaling in fat tissues, 2) in fat tissue-mediated neuromodulation, and 3) in the mRNA translational control in the ovary. Gaining molecular understanding of the role for the ISR in tissue homeostasis will fundamentally inform our approach to experimentally and therapeutically improve tissue function. The advancements from this study will also bear vast pathobiological relevance since ISR dysregulation is associated with an ever-increasing number of diseases, from diabetes to neurodegeneration and cancer.