Cellular and physiological roles of autophagy-related proteins in Drosophila.

由于自噬与衰老、营养代谢、压力和人类疾病有关，一种称为自噬的生物过程引起了人们的极大关注。自噬的字面意思是“自我吞噬”，描述的是细胞降解自身部分以进行回收和再利用的过程。这一过程通常用于维持动态平衡，但也可以作为一种适应性反应，使细胞能够在营养缺乏等应激条件下生存下来。自噬还参与许多发育过程，如细胞生长、组织重塑、细胞碎片的去除、细胞特征的获得和寿命。自噬过程所需的核心自噬相关(ATG)蛋白已经在多种不同的生物体中被确定，但自噬执行其细胞和生理功能的调节输入和分子机制仍然不清楚。我的研究计划的长期目标是在整个有机体的背景下阐明自噬在正常发育中的细胞功能和生理作用。为了实现这一目标，我和我的受训者将利用一个简单的生物模型系统--果蝇，它与人类分享许多遗传和细胞成分，包括自噬所需的成分。这项提议的短期目标是调查性别对自噬和自噬相关蛋白功能的影响。我们最近的初步数据以及文献中的新证据表明，性别影响自噬相关的表型。然而，在大多数自噬研究中，性别的可能影响在很大程度上被忽视了，特别是因为许多自噬研究是在二维细胞培养系统中进行的。在这项研究中，我们将使用果蝇模型系统来确定性别如何影响自噬反应以及核心自噬相关蛋白的功能。我们将阐明导致性别特异性自噬相关表型的分子机制，并首次进行大型无偏见筛查，以确定与性别二态自噬相关表型的潜在新修饰物。总体而言，这些短期目标将有助于重要的新知识，这些知识是我们理解核心自噬相关(ATG)蛋白在整个有机体中的生理作用的长期目标的基础。

A biological process called autophagy has garnered enormous attention due to its association with aging, nutrient metabolism, stress, and human diseases. Autophagy literally means "self-eating" and describes a process in which cells degrade parts of themselves for recycling and re-use. This process typically serves to maintain homeostasis but it can also act as an adaptive response, enabling cells to survive conditions of stress such as nutrient deprivation. Autophagy is also involved in numerous developmental processes such as cell growth, tissue remodeling, removal of cell fragments, acquisition of cellular traits and longevity. The core autophagy-related (Atg) proteins required for the autophagy process have been identified in multiple different organisms, but the regulatory inputs and molecular mechanisms by which autophagy carries out its cellular and physiological functions remain ill defined. The long-term goal of my research program is to elucidate the cellular functions and physiological roles of autophagy in normal development in the context of a whole organism. To achieve this goal, my trainees and I will utilize a simple model organism system, the fruit fly, which shares many genetic and cellular components with humans including those required for autophagy.  The short-term goal of this proposal is to investigate the influence of sex on the function of autophagy and autophagy-related proteins. Our recent preliminary data, along with emerging evidence in the literature, indicate that sex influences autophagy-related phenotypes. However, the possible influence of sex is largely overlooked in the majority of autophagy investigations, especially since many autophagy studies are conducted in two dimensional cell culture systems. In this study, we will use the fruit fly model system to determine how sex influences autophagy responses and the functions of the core autophagy-related proteins. We will elucidate molecular mechanisms that contribute to sex-specific autophagy-related phenotypes, and be the first to perform a large unbiased screen to identify potential new modifiers of sexually dimorphic autophagy-related phenotypes. Overall, these short term goals will contribute important new knowledge that is fundamental to our long term goal of understanding the physiological roles of the core autophagy-related (Atg) proteins in the context of a whole organism.