Collaborative Research: Biophysical and Molecular Mechanisms of Ultrafast Endocytosis at Neuronal Synapses

物理力量决定了活细胞的膜如何改变形状。内吞作用是一种将分子带入细胞所必需的膜过程。病毒通常通过劫持内吞过程进入细胞，因此了解物理力量如何促进膜重塑，特别是内吞作用是至关重要的。内吞作用很重要的一个地方是在神经突触将物质包从一个神经细胞转移到另一个神经细胞。这种类型的内吞作用是如何发生的仍然是一个谜。最近的实验发现了一种新颖的、超快的突触内吞机制，这种机制在50毫秒内发生。然而，超快内吞作用的机制仍然知之甚少。该项目的目标是获得对这种新型内吞途径的机制见解。由于神经突触内吞缺陷可能导致神经退行性疾病，本工作将为了解不同疾病中的突触奠定基础。为了教育公民和吸引年轻人参与科学研究，研究人员将为高中生创造机会，让他们参与以研究为基础的科学活动，在高中发表关于研究的客座讲座，并在实验室接待高中教师。在本研究中，我们将采用协同实验和计算机建模方法来测试这些模型。渡边实验室将进行定位和微扰实验，以揭示分子组织和要求。Agrawal实验室将利用分子信息建立计算模型来测试被动和主动机制，并预测时间尺度。提出的工作将是第一个统一的努力来研究由弹性和耗散力调节的囊泡动力学。此外，所提出的研究将为未来探索膜蛋白动力学和细胞界面重塑提供一个有效的建模框架。

Physical forces determine how the membrane of a living cell changes shape. Endocytosis is a membrane process that is essential for bringing molecules into the cell. Viruses often gain entry into cells by hijacking the endocytic process, and thus it is critical to understand how physical forces contribute to membrane remodeling and, specifically, to endocytosis. One place where endocytosis is important is in the transfer of packets of material from one nerve cell to another at a nerve synapse. How this type of endocytosis occurs remains a mystery. Recent experiments have discovered a novel, ultrafast, endocytic mechanism at synapses that occurs within 50 milliseconds. The mechanisms underlying the ultrafast endocytosis, however, remain poorly understood. The goal of this project is to gain mechanistic insights into this novel endocytic pathway. Since defects in endocytosis at nerve synapses may cause neurodegenerative diseases, the work will lay the foundation to understand synapses in different diseases. To educate citizens and attract young people into science research, the investigators will create opportunities for high-school students to participate in research-based scientific activities, deliver guest lectures about the research at high schools and host high school teachers in the lab.In this research, we will take synergistic experimental and computer modeling approaches to test these models. The Watanabe lab will perform localization and perturbation experiments to reveal the molecular organization and requirements. The Agrawal lab will use the molecular information to build computational modeling to test the passive and active mechanisms and predict the time-scales. The proposed work will be the first unified effort to investigate vesicle dynamics regulated by elastic and dissipative forces. In addition, the proposed research will provide a validated modeling framework for future exploration of membrane-protein dynamics and cellular interface remodeling.