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

在这个项目中，PI将开发新的工具来询问脂质功能，并将它们应用于了解生物系统中组织是如何出现的。细胞及其内部细胞器被称为膜的脂类分子薄片隔开，膜是一系列分子过程的环境。这些膜的化学成分控制着它们的性质，由饮食调节，并且可以通过基因改变。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-脂相互作用如何推动膜域和细胞运输网络的形成。PI将把研究系统整合到一个外联计划中，以改善高中在量化STEM领域的教育，例如物理，目前这一领域在美国人口的许多部分都是落后的。为此，将开发利用细胞膜中发生的过程来通过生物学应用教授物理概念的学习模块。这种方法促进物理和数量生物学的能力将在圣地亚哥地区的学校进行测试，这些学校主要服务于未被充分代表的少数族裔(URM)学生群体。该项目的目标是将膜组织模型从合成模型转化为真实的细胞膜，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个显示微米级横向相分离的真核细胞器：酵母空泡和哺乳动物高尔基体，前者在饮食限制时形成有序的膜域，充当分解代谢的对接部位；后者中类似的结构域可以作为分泌物分类的部位。对于每个隔室，将使用代谢工程策略来开发形成区域的脂质化学计量的定量操作方法。这种方法将允许表征活细胞的膜相特性，并阐明它们是如何调节功能的。这些发现将被用来1)探索脂头基团修饰在结构域形成中的作用，以及2)重建真核进化过程中固醇结构多样化的途径。同时，将开发一个综合教育部分，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学应用相结合。针对圣地亚哥地区高中教师的新的基于课程研究模式的教育计划将增加URM学生在定量科学方面的培训，并由项目人员提供持续的面对面指导。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.