CAREER: Spatiotemporal Regulation of Clathrin-mediated Endocytosis

这个学院早期职业发展(CALEAR)项目旨在了解细胞用来调节膜结合分子进入细胞的吸收的机制。细胞通常使用一种名为笼状蛋白的蛋白质来包裹膜，而膜反过来又吞噬了结合到内化的分子。该项目的结果将提供一个全面的理解，笼络蛋白介导的内化，可以扩展到细胞与其环境的日常相互作用。这项研究计划还将有助于为俄亥俄州哥伦布人口较少地区的高中生建立教育推广活动。为了吸引年轻一代接触科学，将与当地一所免费公立高中合作，组织研究机会和研讨会计划。国际学生联合会将启动一个新的项目，通过替代经验(SERVE)提高STEM的自我效能，通过提高女学生在数学和科学方面的自我效能来缓解STEM领域的性别失衡。国际和平研究所将确保其研究小组中的研究生积极参加外联活动，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桥项目合作，从代表不足的群体中支持和培训硕士水平的学生。尽管是研究最深入的膜转运蛋白，但由于缺乏相关的实验方法来研究分子筛蛋白外壳的结构和时间特性，因此分子筛蛋白介导的内吞机制的基本方面仍不清楚。由PI领导的研究表明，细胞的机械属性决定了胞内网状蛋白涂层的动态和结构属性。在这一职业研究计划的第一部分，PI将表征不同膜张力和曲率水平下内细胞型网状蛋白涂层结构的起始和成熟动力学，以确定决定内细胞型网状蛋白涂层的起始性、稳定性和曲率的因素。PI随后将在与时空张力梯度相关的细胞过程中确定笼状蛋白涂层结构的动力学，以阐明笼状蛋白介导的细胞内转运的异质性的起源。刻画网状蛋白被膜形成的时空规律，并确定其异质性的分子基础，将发展对网状蛋白介导的内吞作用的整体观点和系统水平的理解。这一职业发展计划的长期目标将使研究人员能够描述在细胞和组织水平的形态变化期间机械信号和膜交通之间的相互作用，这些变化对于正常的生物功能是必不可少的。

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.