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

项目摘要 阐明整合应激反应途径在组织稳态中的作用 后生动物已经进化出应激反应途径来对抗内部和外部应激源（例如， 营养缺乏、环境条件变化、有毒物质损害）。整合应激 ISR是一种进化上保守的途径，它介导细胞对环境的适应。 应力自从ISR在酵母中被发现以来，人们一直致力于研究ISR信号转导的作用 介导细胞对外源性应激的反应。在高等生物中，许多特化细胞 这些类型已经进化到依赖ISR来维持体内平衡：值得注意的例子包括 代谢活性细胞如肝细胞和脂肪细胞，高度分泌细胞如胰岛β细胞， 胰腺细胞和具有高蛋白质周转的神经元，如光感受器。我们目前 对ISR信号在维持组织稳态中的理解主要来自表型 功能丧失突变体的观察，但对潜在的分子和细胞 生物学就是这样的规律。该提案旨在获得对精确分子和细胞的新见解， ISR信号在维持组织稳态中的生物学机制。我们将使用 果蝇的脂肪组织和卵巢作为一个发现平台，由于遗传和分子的广度， 可用于操纵这些组织的生物学工具。 ISR信号传导的不同分支在高度保守的转录因子中达到顶峰， ATF 4我们最近描述了果蝇ATF 4在卵子发生调控中的作用。我们的初步 数据显示虽然一些卵子发生缺陷（例如，卵母细胞成熟） 卵巢中对Atf4的自主需求，其他几种（例如，蛋黄蛋白质积累 产卵）是由卵巢周围脂肪组织中的Atf 4非自主地介导的组织。基于 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， 组织非自主地发挥功能。利用我们在分子和细胞生物学方面的广泛背景 技术与强大的果蝇遗传工具，我们将追求三个项目，以建立作用， ISR信号1）在调节脂肪组织中的类固醇激素信号，2）在脂肪组织介导的 神经调节，和3）在卵巢中的mRNA翻译控制。获得分子 对ISR在组织稳态中作用的理解将从根本上为我们的方法提供信息， 在实验上和治疗上改善组织功能。这项研究的进展也将 具有巨大的病理生物学相关性，因为ISR失调与不断增加的 许多疾病，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.