CAREER: Spatiotemporal Regulation of Clathrin-mediated Endocytosis

本学院早期职业发展（Career）项目旨在了解细胞调节膜结合分子进入细胞的机制。细胞通常使用一种叫做网格蛋白的蛋白质来包裹细胞膜，而这种蛋白质反过来又会吞噬那些被吸收的分子。该项目的结果将提供对网格蛋白介导的内化的全面理解，可以扩展到细胞与环境的日常相互作用。该研究项目还将帮助俄亥俄州哥伦布市代表性不足地区的高中生建立教育推广活动。为了吸引年轻一代从事科学，将与当地一所免学费的公立高中合作，组织研究机会和研讨会项目。为了提高女性学生在数学和科学领域的自我效能感，改善STEM领域的性别不平衡，PI将推出“通过替代体验的STEM自我效能感（SERVE）”新项目。PI将确保其研究小组的研究生积极参与外联活动，并培养向非科学受众传达其科学知识和经验所需的技能。PI还将与俄亥俄州立大学硕士到博士的桥梁项目合作，支持和培训来自代表性不足群体的硕士水平的学生。尽管是研究最深入的膜转运蛋白，但由于缺乏实验方法来研究网格蛋白外壳的结构和时间特性的相关性，网格蛋白介导的内吞机制的基本方面仍然不清楚。由PI领导的研究表明，细胞的机械特性决定了内吞网格蛋白外壳的动态和结构特性。在CAREER研究计划的第一部分，PI将在不同的膜张力和曲率水平下表征内吞网格蛋白包被结构的起始和成熟动力学，以确定决定内吞网格蛋白包被的起始、稳定性和曲率的因素。然后，PI将确定网格蛋白包被结构在与时空张力梯度相关的细胞过程中的动力学，以阐明网格蛋白介导的细胞内吞运输异质性的起源。表征网格蛋白外壳形成的时空调控并确定其异质性的分子基础将发展网格蛋白介导的内吞作用的整体观点和系统水平的理解。该职业发展计划的长期目标将使研究人员能够描述细胞和组织水平形态变化过程中机械信号和膜交通之间的相互作用，这些变化对正常的生物功能至关重要。

This Faculty Early Career Development (CAREER) project is designed to understand the mechanisms employed by cells to regulate the uptake of membrane-bound molecules into cells. Cells often use a protein called clathrin to coat membranes which in turn engulf molecules that are bound for internalization. The results of this project will provide a comprehensive understanding of clathrin-mediated internalization that can be extended to the everyday interaction of cells with their environment. This research program will also help establish educational outreach activities for high school students from underrepresented areas of Columbus, OH. To attract young generations to science, research opportunities and a program of seminars will be organized in collaboration with a local tuition-free public high school. The PI will initiate a new program, Self Efficacy in STEM thRough Vicarious Experience (SERVE), to alleviate gender imbalance in STEM fields by boosting female student's self-efficacy in math and sciences. The PI will ensure that the graduate students in his research group will actively participate in the outreach activities and develop skills required for conveying their scientific knowledge and experience to non-scientific audiences. The PI will also work in partnership with the Ohio State University Master's to PhD Bridge Program to support and train a master's level student from underrepresented groups. Despite being the most intensely studied membrane transporters, due to the lack of experimental approaches that allow correlation of structural and temporal properties of clathrin coats, fundamental aspects of clathrin-mediated endocytic mechanism remain unclear. Research led by the PI revealed that the mechanical properties of cells dictate the dynamic and structural properties of endocytic clathrin coats. In the first part of this CAREER research program, the PI will characterize the initiation and maturation dynamics of endocytic clathrin-coated structures at distinct membrane tension and curvature levels to establish the factors determining the initiation, stability and curvature of endocytic clathrin coats. The PI will then determine the dynamics of clathrin-coated structures during cellular processes associated with spatiotemporal tension gradients to elucidate the origin of heterogeneity in clathrin-mediated endocytic trafficking in cells. Characterizing the spatiotemporal regulation of clathrin coat formation and identifying the molecular underpinnings of its heterogeneity will develop a holistic view and systems level understanding of clathrin-mediated endocytosis. The long term goals of this CAREER development plan will allow researchers to delineate the interplay between mechanical cues and membrane traffic during cellular and tissue level morphological changes that are essential for normal biological function.