本群体要解决的关键科学问题是自噬过程中膜的构建与融合。自噬是细胞内高度保守的一种由溶酶体介导的降解途径。自噬在细胞应对胁迫环境及维持细胞代谢稳态过程中发挥重要作用。自噬异常可导致包括神经退行性疾病、肿瘤等多种疾病的发生发展。.本群体成员全部来自中国科学院生物物理研究所，他们在自噬、内质网膜结构功能以及超高分辨显微成像技术等领域做出了突出成绩，近5年来在Cell、Nature Methods、Mol. Cell、Dev. Cell及PNAS等国际著名杂志上发表了一系列与本项目相关论文，产生了重大的学术影响，在多细胞自噬领域处于国际领先水平。.本群体优势互补，协调攻关，拟采用遗传、细胞及超高分辨显微成像技术来解决内质网如何参与自噬小体的形成以及自噬小体的成熟机制。对多细胞生物自噬过程的研究不仅能帮助我们解析自噬异常引起疾病的致病机理，也将为诊断和治疗提供关键的理论依据和药物设计的重要靶点。

Autophagy is an evolutionarily conserved lysosome-mediated degradation process. Autophagy acts as a cell survival mechanism in response to various metabolic stresses and also functions as a quality control system to maintain cellular homeostasis. Dysfunction of autophagy has been linked to the development of a broad range of human diseases, including tumorigenesis and neurodegeneration. The autophagy process involves a series of membrane remodeling and fusion processes. However, very little is known about the membrane origin of autophagosomes and the fusion specificity of autophagosomes with endosomes during autophagosome maturation. In this proposal, we will use C. elegans as a model system to perform genetic screens to identify genes essential for the autophagy pathway and also to isolate suppressors of known autophagy genes. Then we will use a state-of-the-art super-resolution imaging system to investigate membrane remodeling in the autophagy pathway, especially the formation of autophagosomes from the endoplasmic reticulum (ER) and autophagosome maturation. .The four labs involved in this proposal, all from the Institute of Biophysics, Chinese Academy of Sciences, are leading scientists working at the forefront of their fields. Dr. Hong Zhang has made seminal contributions in the autophagy field. His group demonstrated that autophagy selectively removes a variety of protein aggregates during C. elegans embryogenesis and also revealed molecular mechanisms that confer the degradation specificity and efficiency of autophagic degradation of protein aggregates. Dr. Zhang’s lab also isolated multiple metazoan-specific autophagy genes and further showed that mice deficient in these autophagy genes exhibit neurodegenerative diseases. Dr. Junjie Hu studied the structures and functions of the endoplasmic reticulum, discovered proteins that mediate homotypic fusion of the ER and provided important mechanistic insights. Dr. Tao Xu’s lab revealed the regulatory mechanisms involved in the docking, priming and fusion of different secretary vesicles, particularly large dense-core vesicles (DCVs) and GLUT4 storage vesicles (GSVs). Dr. Tao Xu also developed new methods and instruments to improve the performance of currently used diffraction-unlimited microscopy especially in spatial resolution, temporal resolution and labeling technology. Dr. Pingyong Xu has developed excellent photoactivatable and photoswitchable fluorescent proteins for diffraction-unlimited super-resolution imaging. .These four labs will collaboratively investigate the formation and fusion of membranes in the autophagy pathway. This is an interdisciplinary area covering autophagy, membrane dynamicsand super-resolution imaging. Understanding the molecular mechanism of autophagy will help us to understand the pathogenesis of diseases associated with dysregulation of cellular metabolism and also provide insights into the design of strategies for therapeutic treatment.