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

阐明综合应激反应途径在组织稳态中的作用

• 批准号: 10710860
• 负责人: Deepika Vasudevan
• 金额: $ 39.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-13 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710860
• 关键词: Adipocytes; Biological; Cells; Cellular Stress; Cellular biology; Clinical; Data; Dedications; Defect; Diabetes Mellitus; Disease; Drosophila genus; Egg Yolk Proteins; Fatty acid glycerol esters; Genetic; Health; Hepatocyte; Homeostasis; Islet Cell; Knowledge; Malignant Neoplasms; Mediating; Metabolic; Mission; Molecular; Molecular Biology; National Institute of General Medical Sciences; Nerve Degeneration; Neurons; Oogenesis; Organism; Ovary; Pancreas; Pathology; Pathway interactions; Peripheral; Phenotype; Photoreceptors; Play; Regulation; Research; Role; Secretory Cell; Stress; Stress Response Signaling; Techniques; Testing; Therapeutic; Tissues; Yeasts; biological adaptation to stress; cell type; combat; egg; hormonal signals; improved; insight; loss of function; mRNA Translation; mutant; neuroregulation; nutrient deprivation; oocyte maturation; protein degradation; response; sensor; steroid hormone; stressor; tool; transcription factor

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.

项目摘要 阐明综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压力源（例如， 营养缺乏、环境条件变化、有毒物质侵害）。综合应力 反应（ISR）是一种进化上保守的途径，介导细胞对环境的适应。 压力。自从在酵母中发现 ISR 信号传导以来，人们一直致力于研究 ISR 信号传导的作用 介导细胞对外源应激的反应。在高等生物中，许多特化细胞 类型已经进化到依赖 ISR 来维持体内平衡：这方面的著名例子包括 代谢活跃的细胞，如肝细胞和脂肪细胞，高分泌细胞，如 b 胰岛 胰腺细胞和具有高蛋白质周转率的神经元，例如光感受器。我们目前的 对 ISR 信号在维持组织稳态方面的理解很大程度上来自于表型 对功能丧失突变体的观察，但对潜在的分子和细胞知之甚少 这种调节的生物学。该提案旨在获得对精确分子和细胞的新见解 ISR 信号控制维持组织稳态的生物学机制。我们将使用 由于遗传和分子的广泛性，果蝇脂肪组织和卵巢作为一个发现平台 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 在卵子发生调节中的作用。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）是由 卵巢对 Atf4 的自主需求，以及其他一些（例如卵黄蛋白积累、卵子 产蛋）是卵巢周围脂肪组织中 Atf4 非自主介导的组织。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，该传感器通知外周 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，我们将开展三个项目来确立果蝇的作用 ISR 信号传导 1) 调节脂肪组织中的类固醇激素信号传导，2) 脂肪组织介导的信号传导 神经调节，3) 卵巢中 mRNA 翻译控制。获得分子 了解 ISR 在组织稳态中的作用将从根本上指导我们的方法 通过实验和治疗改善组织功能。这项研究的进展也将 具有广泛的病理生物学相关性，因为 ISR 失调与不断增加的 多种疾病，从糖尿病到神经退行性疾病和癌症。