Interactions of Cholesterol and Gangliosides with Lipids

University Of Chicago, Chicago IL

Investigators

Abstract

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.