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

一种被称为自噬的生物过程由于与衰老、营养代谢、压力和人类疾病有关而引起了极大的关注。自噬字面上的意思是“自我吞噬”，描述了细胞降解自身部分以回收和再利用的过程。这个过程通常用于维持体内平衡，但它也可以作为一种适应性反应，使细胞能够在营养剥夺等压力条件下生存。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、细胞特性的获得和寿命。自噬过程所需的核心自噬相关（Atg）蛋白已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控输入和分子机制仍未明确。我的长期研究目标是阐明自噬在整个生物体正常发育过程中的细胞功能和生理作用。为了实现这一目标，我的学员和我将利用一个简单的模式生物系统，果蝇，它与人类共享许多遗传和细胞成分，包括自噬所需的成分。

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.