Regulation of autophagy during animal development

动物发育过程中自噬的调控

• 批准号: 10368964
• 负责人: Eric H Baehrecke
• 金额: $ 63.32万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368964
• 关键词: Address; Animals; Autophagocytosis; Biological; Cells; Cessation of life; Complement; Defect; Development; Disease; Drosophila genus; Enterocytes; Genetic; Genomics; Health; Human; Inflammatory; Intestines; Knowledge; Lead; Lysosomes; Malignant Neoplasms; Mammals; Midgut; Mitochondria; Modeling; Nerve Degeneration; Pathway interactions; Play; Process; Proteins; Regulation; Research; Resolution; Role; Salivary Glands; Signal Pathway; Signal Transduction; System; Therapeutic; Ubiquitin; Yeasts; base; cell type; design; human disease; insight; interest; novel; nutrient deprivation; programs; receptor; tool

ABSTRACT Autophagy is used by all cells to deliver cytoplasmic material to the lysosome for degradation. Significantly, autophagy has been implicated in several human diseases, including inflammatory disorders, cancer and neurodegeneration. Most of what we know about the regulation of autophagy is based on pioneering studies in yeast that defined the core autophagy machinery, but recent studies in animals have revealed that autophagy can possess different regulatory mechanisms in distinct cell types. Our research program aims to understand how autophagy is regulated in 2 cell types during development of Drosophila. This system possesses several advantages for these studies, including robust genetic, genomic and cell biological tools that enable sophisticated cellular analyses at single cell resolution. We have focused on studying autophagy in dying larval salivary gland cells and midgut enterocyte cells of the intestine as models. Both salivary gland and midgut cells require autophagy for proper death and degradation, but use entirely different mechanisms for the activation of autophagy. Salivary gland autophagy is regulated by an ancient inflammatory signaling pathway that includes the complement factor Mcr and the engulfment receptor Draper, but this pathway is not required for autophagy in either fatbody cells following nutrient deprivation or midgut cells of the intestine during development. By contrast, midgut cells of the intestine require a ubiquitin-dependent autophagy program that interfaces with mitochondrial dynamics through the novel Vps13D protein. Significantly, Vps13D is not required for autophagy in either fatbody or salivary gland cells. Our future research program contains 4 projects that will address key questions in the autophagy field. What is the role of inflammatory signaling in developmental autophagy? What is the role of mitochondrial dynamics in autophagy? What is the role of ubiquitin in autophagy? What is the role of previously undiscovered pathways in context-specific regulation of autophagy? These proposed studies will address a critical gap in our knowledge about the cell context-specific mechanisms that regulate autophagy within an animal. Given the strong conservation of autophagy mechanisms between Drosophila and mammals, we expect that what we discover will provide insight into the diversity of mechanisms that control autophagy in humans, and how alterations in autophagy in different cell contexts may lead to disease. Furthermore, an understanding of the diversity of mechanisms that control autophagy in animals is essential knowledge for the design of rationale strategies to target autophagy for disease therapies.

摘要 自噬被所有细胞用于将细胞质物质递送到溶酶体进行降解。 值得注意的是，自噬与几种人类疾病有关，包括炎症性疾病， 疾病、癌症和神经变性。我们所知道的大多数关于 自噬是基于酵母中的开创性研究，其定义了核心自噬机制， 但最近的动物研究表明，自噬可以具有不同的调控机制， 不同细胞类型的机制。我们的研究项目旨在了解自噬是如何 在果蝇发育过程中的2种细胞类型的调控。该系统具有多个 这些研究的优势，包括强大的遗传，基因组和细胞生物学工具， 能够以单细胞分辨率进行复杂的细胞分析。我们专注于研究 死亡幼虫唾液腺细胞和肠中肠上皮细胞的自噬， 模型唾液腺细胞和中肠细胞都需要自噬才能正常死亡， 降解，但使用完全不同的机制激活自噬。唾液 腺体自噬是由一个古老的炎症信号通路调节的， 补体因子Mcr和吞噬受体德雷珀，但这一途径不是必需的， 营养剥夺后脂肪体细胞或肠中肠细胞中的自噬 在发展过程中。相比之下，肠道的中肠细胞需要一种遍在蛋白依赖性的 自噬程序，通过新的Vps13D与线粒体动力学接口 蛋白值得注意的是，Vps13D不是脂肪体或唾液腺中自噬所必需的 细胞我们未来的研究计划包括4个项目，将解决关键问题， 自噬场炎症信号在发育性自噬中的作用是什么？什么 线粒体动力学在自噬中的作用泛素在自噬中的作用是什么？ 以前未发现的通路在特定环境下调节的作用是什么？ 自噬这些拟议中的研究将解决我们对细胞知识的一个关键空白 调节动物体内自噬的特定机制。考虑到强劲的 保护果蝇和哺乳动物之间的自噬机制，我们预计， 我们的发现将为深入了解控制自噬的机制的多样性提供帮助。 人类，以及不同细胞环境中自噬的改变如何导致疾病。 此外，了解控制动物自噬的机制的多样性， 是设计针对疾病自噬的基本策略的基本知识 治疗