Regulation of autophagy during animal development

动物发育过程中自噬的调控

• 批准号: 10592375
• 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/10592375
• 关键词: Animals; Autophagocytosis; Biological; Cells; Cessation of life; Complement; Cytoplasm; Defect; Development; Disease; Drosophila genus; Enterocytes; Fat Body; Genetic; Genomics; Health; Human; Inflammatory; Intestines; Knowledge; 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; 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.

抽象的 所有细胞都使用自噬将细胞质材料传递到溶酶体以降解。 值得注意的是，自噬已与几种人类疾病有关，包括炎症 疾病，癌症和神经退行性。我们对监管的大多数 自噬是基于定义核心自噬机械的酵母的开创性研究， 但是最近对动物的研究表明，自噬可以具有不同的调节 不同细胞类型的机制。我们的研究计划旨在了解自噬的 在果蝇发育过程中以两种细胞类型的调节。该系统拥有几个 这些研究的优势，包括可靠的遗传，基因组和细胞生物学工具 在单细胞分辨率下实现复杂的细胞分析。我们专注于学习 垂死的幼虫唾液腺细胞和肠中肠肠细胞的自噬作为 型号。唾液腺和中肠细胞都需要自噬以适当死亡，并且 退化，但使用完全不同的机制来激活自噬。唾液 腺体自噬受到古老的炎症信号通路的调节，其中包括 补体因子MCR和吞噬受体draper，但是这种途径不需要 养分剥夺后的脂肪细胞或肠中肠细胞的自噬 在开发过程中。相比之下，肠中肠细胞需要泛素依赖性 自噬程序通过新颖的VPS13D与线粒体动力学接口 蛋白质。值得注意的是，在脂肪或唾液腺中自噬不需要VPS13D 细胞。我们未来的研究计划包含4个项目，这些项目将在 自噬领域。炎症信号在发育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？ 以前未被发现的途径在上下文特定的调节中的作用是什么 自噬？这些拟议的研究将解决我们有关细胞的重要差距 调节动物内自噬的上下文特异性机制。鉴于强者 保护果蝇和哺乳动物之间的自噬机制，我们希望 我们发现的内容将洞悉控制自噬的机制的多样性 人类以及在不同细胞环境中自噬的变化如何导致疾病。 此外，了解控制动物自噬的机制多样性 是设计靶向自噬的基本原理策略的基本知识 疗法。