CAREER: Structure, function, and evolution of lipid domains in living cell membranes

职业：活细胞膜脂质结构域的结构、功能和进化

• 批准号: 2046303
• 负责人: Itay Budin
• 金额: $ 89.87万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2046303&HistoricalAwards=false
• 关键词: CAREER; Structure; function; evolution; lipid

In this project, the PI will develop new tools for interrogating lipid function and apply them to understanding how organization emerges in biological systems. Cells and their internal organelles are compartmentalized by thin sheets of lipid molecules called membranes, which serve as the environment for a range of molecular processes. The chemical composition of these membranes controls their properties, is mediated by diet, and can be genetically altered. Understanding how lipid composition impacts cellular processes is thus of broad importance. The project’s research will test how specific lipid-lipid interactions drive the formation of membrane domains and cellular transport networks. The PI will integrate research systems into an outreach program to improve high school education in quantitative STEM fields such as physics, which is currently lagging in many segments of the American population. For this, learning modules will be developed that harness processes occurring in cell membranes to teach physics concepts through biological applications. The ability of this approach to promote physics and quantitative biology will be tested in San Diego-area schools that primarily serves an underrepresented minority (URM) student population.The goal of the project is to translate models of membrane organization from synthetic models to real cell membranes, where their biological roles can be evaluated. The project’s research aims harness two eukaryotic organelles that display micron-scale lateral phase separation: the yeast vacuole, which patterns into ordered membrane domains that act as catabolic docking sites upon diet restriction, and the mammalian Golgi, in which similar domains could act as sites of secretory cargo sorting. For each compartment, methods for the quantitative manipulation of domain-forming lipid stoichiometry will be developed using metabolic engineering strategies. This approach will allow characterization of membrane phase properties in living cells and elucidation of how they modulate function. Findings will then be harnessed to 1) explore the function of lipid head-group modifications in domain formation and 2) reconstruct pathways for the diversification of sterol structure during eukaryotic evolution. In parallel, an integrative educational component will be developed that uses cell membranes as an instructional system to integrate concepts in the quantitative sciences with biological applications for high schoolers. The new Lesson Study model-based education program for San Diego-area high school teachers will increase training in the quantitative sciences by URM students and provide continuing in-person mentorship by project personnel.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.

在这个项目中，PI将开发用于询问脂质功能的新工具，并将其应用于了解生物系统中的组织如何出现。细胞和它们的内部细胞器被称为膜的脂质分子薄片分隔开，膜充当一系列分子过程的环境。这些膜的化学成分控制着它们的特性，由饮食介导，并且可以遗传改变。因此，了解脂质成分如何影响细胞过程具有广泛的重要性。该项目的研究将测试特定的脂质-脂质相互作用如何驱动膜结构域和细胞运输网络的形成。PI将把研究系统整合到一个外展计划中，以改善物理等定量STEM领域的高中教育，目前这一领域在美国人口的许多部分都处于落后状态。为此，将开发学习模块，利用细胞膜中发生的过程，通过生物应用教授物理概念。这种方法促进物理学和定量生物学的能力将在圣地亚哥地区的学校进行测试，主要服务于代表性不足的少数民族（URM）的学生群体。该项目的目标是将膜组织模型从合成模型转换为真实的细胞膜，在那里可以评估它们的生物学作用。该项目的研究目的是利用两种显示微米级横向相分离的真核细胞器：酵母液泡，其模式为有序的膜结构域，在饮食限制时作为分解代谢对接位点，以及哺乳动物高尔基体，其中类似的结构域可以作为分泌货物分选的位点。对于每个隔室，将使用代谢工程策略开发用于结构域形成脂质化学计量的定量操作的方法。这种方法将允许活细胞中的膜相特性的表征和阐明它们如何调节功能。研究结果将用于1）探索脂质头基修饰在结构域形成中的功能，2）重建真核生物进化过程中甾醇结构多样化的途径。同时，将开发一个综合教育组件，使用细胞膜作为教学系统，将定量科学中的概念与高中生的生物应用相结合。为圣地亚哥地区高中教师提供的新的基于课程研究模型的教育计划将增加URM学生在定量科学方面的培训，并提供项目人员的持续亲自指导。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。