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

物理力决定了活细胞膜如何改变形状。 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，因此了解物理力如何促进膜重塑，特别是内吞作用至关重要。内吞作用重要的一个地方是在神经突触处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如何发生仍然是一个谜。最近的实验发现了一种新的，超快的，突触内吞机制，发生在50毫秒内。然而，超快内吞作用的机制仍然知之甚少。这个项目的目标是获得这种新的内吞途径的机制见解。由于神经突触内吞作用的缺陷可能导致神经退行性疾病，这项工作将为了解不同疾病中的突触奠定基础。 为了教育公民，吸引年轻人参与科学研究，研究人员将创造机会让高中生参与基于研究的科学活动，在高中提供关于研究的客座讲座，并在实验室接待高中教师。在这项研究中，我们将采取协同实验和计算机建模的方法来测试这些模型。Watanabe实验室将进行定位和扰动实验，以揭示分子组织和要求。Agrawal实验室将使用分子信息建立计算模型，以测试被动和主动机制并预测时间尺度。拟议的工作将是第一个统一的努力，调查囊泡动力学调节的弹性和耗散力。此外，拟议的研究将提供一个有效的建模框架，为未来探索膜蛋白质动力学和细胞界面重塑。

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.