Interactions of Cholesterol and Gangliosides with Lipids

对脂筏的研究已经引起了生物学家和物理学家的注意，研究人员使用了模型脂类系统以及天然生物膜来更好地了解这些实体。据推测，脂筏的形成是由于脂类和胆固醇之间的复杂形成，而脂类和胆固醇之间的相互作用的阐明构成了这个项目的基础。该项目将使用3种不同类型的模型系统：单层、双层和天然红细胞膜，以及一套生物物理技术(表面压力测量、荧光、β-环糊精解吸分析、掠入射X射线衍射、X射线反射率以及细胞内位移分析)，以探索所涉及的相互作用的性质。这项研究的目标分为三个方面：(1)脂类和胆固醇缩合物的性质。它们的热稳定性如何？它们只能在胆固醇和高熔点脂肪之间形成吗？除了络合物形成模型外，结构和化学活性数据是否与其他关于脂类/胆固醇相互作用的模型一致？(2)膜嵌入剂。有效的膜嵌入剂能够破坏脂类和胆固醇之间的相互作用，其结构属性是什么？嵌入物疏水性的改变将如何影响其置换性能？其他类固醇能有效替代胆固醇吗？(3)涉及神经节苷脂的脂类排序。神经节苷脂被认为富含在脂筏中，如何影响其周围脂类的组织？它们与高熔点脂肪的协调方式与胆固醇相似吗？或者它们形成了其他类型的结构？成功解决这些问题将有助于阐明脂类和甾醇之间的相互作用以及涉及脂类和神经节苷脂的相互作用。它还将弥合模型和自然膜系统之间的差距，并解决在各种模型系统中发现的一些看似不一致的问题。从这项工作中获得的知识将极大地加深我们对脂筏的基本了解。这些研究活动将为研究人员在一个高度交叉的领域提供培训机会，并有助于培养下一代跨学科研究科学家。该项目将进一步加强膜生物物理学研究生课程的内容，以及新的生物物理学跨学科学位授予方案的课程开发。除了研究生和博士后，研究机会将扩大到高中、本科生、暑期研究以及国际交换生。PI已经带头并将继续参与为期7周的夏季研究项目Summer Link，将来自芝加哥大学实验室学院的10名高三学生安排在芝加哥大学生物科学部和物理科学部的实验室中。早期接触研究有助于吸引这些年轻学生考虑从事科学工作。国际和平研究所将继续接待本科生和REU学生在实验室进行研究。国际研究合作将通过PI与香港中文大学建立的暑期交换生项目以及芝加哥大学MRSEC的智利交换项目来促进。将通过外展活动向学童传授科学，特别是跨学科科学的概念。国际和平研究所致力于增加女性在学术科学中的代表性。将努力通过PI与教务长办公室的合作以及她作为芝加哥大学物理学部自然科学妇女委员会主席的参与，努力解决妇女在学术科学方面的机会。

The study of lipid rafts has attracted the attention of biological and physical scientists alike, and researchers have used model lipid systems as well as natural biological membranes to try to better understand these entities. It has been postulated that lipid rafts form due to complex formation between lipids and cholesterol, and elucidation of the interactions between lipids and cholesterol has formed the basis for this project. The project will use 3 different types of model system: monolayers, bilayers, and natural membranes of red blood cells, and a suite of biophysical techniques (surface-pressure measurements, fluorescence, beta-cyclodextrin desorption assays, grazing incidence x-ray diffraction, x-ray reflectivity as well as displacement assays in cells) to probe the nature of the interactions involved. The objectives of the research fall into three areas: (1) Nature of Condensed Complexes of Lipids and Cholesterol. What is their thermal stability? Can they only be formed between cholesterol and high melting point lipids? Are the structural and chemical activity data consistent with other models on lipid/cholesterol interactions besides the complex formation model? (2) Membrane Intercalators. What are the structural attributes of an effective membrane intercalator capable of disrupting the interactions between lipids and cholesterol? How would alterations in the hydrophobicity of the intercalator affect its displacement performance? Would other sterols be effective in displacing cholesterol? (3) Lipid Ordering Involving Gangliosides. How do gangliosides, thought to be enriched in lipid rafts, affect the organization of their surrounding lipids? Do they coordinate with high melting point lipids in a similar fashion as cholesterol? Or do they form other types of structures? The success in addressing these questions will help elucidate interactions between lipids and sterols as well as those involving lipids and gangliosides. It will also bridge the gap between model and natural membrane systems, and resolve some of the seeming inconsistencies found in various model systems. The knowledge gained from this work will greatly add to our fundamental understanding of lipid rafts.The research activities will provide training opportunities for the researchers in a highly interdisciplinary area, and will help train the next generation of interdisciplinary research scientists. The project will further enhance the content of a graduate course in membrane biophysics, as well as the curriculum development of a new interdisciplinary degree-granting program in Biophysical Sciences. Apart from graduate students and postdocs, research opportunities will be extended to high school, undergraduate, summer research as well as international exchange students. The PI has spearheaded and will continue to participate in a 7-week summer research program, Summer Link, placing 10 high school seniors from the University of Chicago Laboratory Schools in laboratories across the Biological Sciences Division and the Physical Sciences Division at the University of Chicago. An early exposure to research can help entice these young students to consider a career in science. The PI will continue to host undergraduates and REU students for research in the laboratory. International research collaboration will be promoted via a summer exchange student program established by the PI with the Chinese University of Hong Kong, as well as the Chile Exchange Program of the University of Chicago MRSEC. Science, especially the concept of interdisciplinary science, will be brought to schoolchildren through outreach activities. The PI is committed to increasing the representation of women in academic science. Efforts will be made to address the opportunities for women in academic science through the PI's work with the Office of the Provost and her involvement as the Chair of the Women in Physical Sciences Committee of the Physical Sciences Division at the University of Chicago.