Spectrin as a mechanosensitive hub integrating polarity, growth and trafficking

血影蛋白作为整合极性、生长和运输的机械敏感中心

• 批准号: 1952922
• 负责人: Claire Thomas
• 金额: $ 86.27万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1952922&HistoricalAwards=false
• 关键词: Spectrin; mechanosensitive; hub; integrating; polarity

This project will increase our understanding of how cells coordinate their structure and their growth. Cells, which are the fundamental unit of life, have a defined shape built by a set of internal structural proteins known as the cytoskeleton. Cells also grow, divide, and sense their mechanical environment. Some of these functions are also dependent on cytoskeletal proteins. In this project, the researches will examine the mechanism by which spectrin, a giant cytoskeletal protein, performs its functions in cell growth, division and mechano-sensing. Associated with this research, the principle investigator and her team will engage in outreach activities that promote STEM careers including leading an effort in the College of Science to bring a mobile science classroom to central/eastern Pennsylvania and working with a local science museum. These activities will provide high-impact STEM experiences to K-12 students, as well as bring teacher professional development to rural and inner-city areas. The principle investigator’s lab will also participate in programs that promote women, minority and LGBTQ+ undergraduate participation in research, and bring research projects into undergraduate teaching laboratories, enhancing undergraduate education. Cellular growth must be integrated with the mechanical properties of cellular structures. Spectrins are giant cytoskeletal proteins with two contrasting activities. They are best known for their ability to form fishing net-like structural networks with F actin at the cell cortex that can undergo mechanical stretching. However, spectrins have recently also been shown to modulate protein trafficking in the endosome system. The molecular regulation that balances these two activities is unknown. Through the study of Beta-H-spectrin in epithelial cells of Drosophila melanogaster, this project will test two competing hypotheses to elucidate the molecular mechanisms by which spectrins coordinate mechanosensing and growth control in the cell. One approach will test the hypothesis that tension in the spectrin network plays a role in the relocation of the membrane protein Crumbs and in its control of the growth-inhibiting Hippo pathway. The second approach tests the hypothesis that spectrin networking contributes to the regulation of Crumbs/Hippo control of cell growth in endosomes. The project will use advanced STORM imaging and protein biochemistry to determine the geometry of the spectrin network and the extent to which it is stretched by changes in Myosin II-generated tension. Protein biochemistry, genetics and cell biology will also be used to further understand the role of spectrin and its associated proteins in the regulation of endosomal protein trafficking. Overall the results of this project will generate new paradigms for how spectrins function in the control of cellular growth.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目将增加我们对细胞如何协调其结构和生长的理解。细胞是生命的基本单位，具有由一组被称为细胞骨架的内部结构蛋白构建的定义形状。细胞还会生长，分裂并感知其机械环境。其中一些功能也取决于细胞骨架蛋白。在该项目中，研究将研究谱系（一种巨大的细胞骨架蛋白）在细胞生长，分裂和机理感应中发挥作用的机制。与这项研究相关的是，主要调查员和她的团队将开展宣传活动，以促进STEM职业，包括领导科学学院的努力，将移动科学教室带到宾夕法尼亚州中部/东部，并与当地科学博物馆合作。这些活动将为K-12学生提供高影响力的STEM体验，并将教师专业发展带入艰难的城市地区。主要研究者实验室还将参加促进妇女，少数群体和LGBTQ+本科参与研究的计划，并将研究项目带入本科教学实验室，并增强本科教育。细胞生长必须与细胞结构的机械性能集成。光谱是具有两种对比活性的巨型细胞骨架蛋白。他们以其在细胞皮质上形成艾肌动蛋白的渔网状结构网络的能力而闻名，可以在细胞皮质中进行机械拉伸。然而，最近还显示，光谱也可以调节内体系统中的蛋白质运输。平衡这两种活动的分子调节尚不清楚。通过研究果蝇的上皮细胞中的β-H-谱蛋白，该项目将检验两个竞争的假设，以阐明光谱素质在细胞中协调机制和生长控制的分子机制。一种方法将检验以下假设：光谱网络中的张力在膜蛋白碎屑的重定位以及控制抑制生长河马途径的情况下起作用。第二种方法检验了光谱网络的假设有助于调节内体中细胞生长的Crumbs/Hippo控制。该项目将使用先进的风暴成像和蛋白质生物化学来确定谱蛋白网络的几何形状，并通过肌球蛋白II产生的张力的变化来延伸它的程度。蛋白质生物化学，遗传学和细胞生物学也将用于进一步了解谱蛋白及其相关蛋白在调节内体蛋白运输中的作用。总体而言，该项目的结果将产生新的范式，以实现光谱在控制细胞生长中的功能。该奖项反映了NSF的法定使命，并通过使用基金会的知识分子优点和更广泛的审查标准评估来诚实地获得支持。