Regulation of autophagy during animal development

摘要 自噬被所有细胞用来将细胞质物质运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 疾病、癌症和神经退行性变。我们所知道的关于监管的大部分 自噬是基于对酵母的开创性研究，这些研究定义了核心的自噬机制， 但最近在动物身上的研究表明，自噬可以具有不同的调控 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 在果蝇发育过程中受两种细胞类型的调控。这个系统有几个 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 以单细胞分辨率实现复杂的细胞分析。我们一直专注于研究 肠道垂死幼虫唾液腺细胞和中肠肠道细胞的自噬 模特们。唾液腺和中肠细胞都需要自噬才能正常死亡 但使用完全不同的机制来激活自噬。唾液 腺体自噬由一条古老的炎症信号通路调节，该通路包括 补体因子MCR和吞噬受体Draper，但这一途径不是必需的 营养剥夺后脂肪小体细胞或肠道中肠细胞的自噬 在开发过程中。相比之下，肠道的中肠细胞需要依赖泛素的 通过新的Vps13D与线粒体动力学相结合的自噬程序 蛋白。值得注意的是，Vps13D在脂肪体或唾液腺中的自噬都不是必需的 细胞。我们未来的研究计划包括4个项目，将解决 自噬区域。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起作用吗？泛素在自噬中的作用是什么？ 先前未发现的通路在特定背景调控中的作用是什么？ 自噬？这些拟议的研究将解决我们对细胞了解的一个关键差距 调节动物体内自噬的特定于环境的机制。考虑到强者 果蝇和哺乳动物之间自噬机制的保守，我们预计 我们的发现将提供对控制自噬的机制的多样性的洞察 人类，以及在不同细胞环境中自噬的变化如何可能导致疾病。 此外，对控制动物自噬的各种机制的理解 是设计针对疾病自噬的基本策略的基本知识 治疗。

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.