The Interplay Between Membrane Structure and Protein Interactions

在这个研究项目中，PI将建立一个全面的范式，以了解膜结合肽和蛋白质区分膜的机制。这是生物学中一个根本性的重要问题，将在免疫应答的背景下进行探索，重点关注免疫应答期间膜的免疫靶向的两个典型例子。这种模式将通过为理解蛋白质如何选择性地识别膜靶点提供基础来推进多学科的知识。该项目还将形成多种实验技术之间的联盟，从而为许多科学领域做出贡献，包括但不限于分子免疫学，膜生物物理学，界面X射线和中子散射。拟议的研究活动将提供高度跨学科领域的培训机会，并将有助于培养下一代跨学科科学家。PI将进一步加强膜生物物理学研究生课程的内容，以及生物物理科学新的跨学科学位授予计划的课程开发。除了研究生和博士后，研究机会将扩展到合格的高中，本科，暑期研究以及国际交换生。PI已经率先并将继续运行一个为期7周的夏季研究计划，将14名来自芝加哥大学实验学校的高中毕业生放在芝加哥大学生物和物理科学系的实验室中。这是希望早期接触研究可以帮助吸引这些年轻的学生考虑在科学事业。PI将继续接待本科生和REU学生在实验室进行研究。科学，特别是跨学科科学的概念，将通过外展活动，包括参加“物理与爆炸！并向低年级学生进行科学演示。PI致力于增加妇女在学术科学中的代表性。通过PI与教务长办公室的合作以及她参与芝加哥大学物理科学部门委员会的妇女以及大芝加哥地区的芝加哥妇女STEM组织，将努力解决妇女在学术科学中的机会。对膜双层的理解已经从简单的马赛克系统发展到具有复杂异质横向结构的系统。阐明了膜内不同的脂质物质如何相互作用，以及这些相互作用如何引起脂质膜的定义性质，为脂质膜的组织和结构提供了基本的见解。该项目利用膜系统表征方面的专业知识，使用模型膜系统，并利用一套生物物理技术（表面压力测量，光学显微镜，荧光结合测定，原子力显微镜，X射线和中子散射），为两个基本的和与生物相关的问题提供新的视角：（1）膜特性如何影响与膜靶向肽和蛋白质的相互作用？(2)肽和蛋白质的相互作用如何改变给定膜的性质？该项目专门解决了免疫应答背景下的这些核心问题，重点是免疫应答期间膜的免疫靶向的两个典型例子：抗菌肽（AMP）对病原体膜的破坏和对暴露在宿主细胞胞外小叶上的磷脂酰丝氨酸（PS）脂质的识别作为免疫调节的效应子。AMP和外周PS膜结合蛋白都被假设为利用对膜特性差异的敏感性来介导其差异识别特性。因此，本项目的主要重点是首先建立代表性AMP（protegrin-1）和PS受体家族（T细胞免疫球蛋白和含粘蛋白或TIM）对基本膜特性的敏感性。此外，该项目还旨在进一步了解这些肽和蛋白质的相互作用如何改变潜在的膜特性。

In this research project, the PI will establish a comprehensive paradigm for understanding the mechanisms by which membrane-binding peptides and proteins distinguish one membrane from another. This is a fundamentally important question in biology and will be explored in the context of immune response, focusing on two canonical examples of immune targeting of membranes during immune response. This paradigm will advance knowledge in multiple disciplines by providing a foundation for understanding how proteins selectively recognize membrane targets. The project will also form a union between a multitude of experimental techniques and thereby contribute to many scientific fields including, but not limited to, molecular immunology, membrane biophysics, and interfacial x-ray and neutron scattering.The proposed research activities will provide training opportunities in a highly interdisciplinary area, and will help train the next generation of interdisciplinary scientists. The PI 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 qualified high school, undergraduate, summer research as well as international exchange students. The PI has spearheaded and will continue to run a 7-week summer research program, placing 14 rising high school seniors from the University of Chicago Laboratory Schools in laboratories across the Biological and Physical Sciences Divisions at the University of Chicago. It is the hope that an early exposure to research can help entice these young students to consider a career in science. The PI will continue to host undergraduate and REU student for research in the laboratory. Science, especially the concept of interdisciplinary science, will be brought to school children through outreach activities, including participating in 'Physics with a Bang!', and performing science demonstrations to lower school students. 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 Provost Office and her involvement in the Women in Physical Sciences Division Committee at the University of Chicago as well as the Chicago Women in STEM organization in the Greater Chicago Area.The understanding of the membrane bilayer has evolved from a simple mosaic system to one with a complicated heteregeneous lateral structure. The elucidation of how different lipids species within a membrane interact with one another, and how these interactions give rise to the defining properties of lipid membranes has provided fundamental insight into the organization and structure of lipid membranes. The project leverages expertise in the characterization of membrane systems, using model membrane systems and exploiting a suite of biophysical techniques (surface-pressure measurements, optical microscopy, fluorescence binding assays, atomic force microscopy, x-ray and neutron scattering) to provide new perspectives on two fundamental and reciprocally related questions:(1) How do membrane properties influence interactions with membrane targeting peptides and proteins?(2) How does the interaction of peptides and proteins alter the properties of a given membrane?The project specifically addresses these central questions in the context of immune response, focusing on two canonical examples of immune targeting of membranes during immune response: the disruption of pathogenic membranes by antimicrobial peptides (AMPs) and the recognition of phosphatidylserine (PS) lipids exposed on the extracellular leaflet of host cells as an effector of immune regulation. Both AMPs and peripheral PS membrane binding proteins have been hypothesized to employ sensitivity to differences in membrane properties to mediate their differential recognition properties. Thus the primary focus of this project is to first establish the sensitivities of a representative AMP (protegrin-1) and PS receptor family (T-cell Immunoglobulin and Mucin-containting or TIM) to fundamental membrane properties. Additionally, the project also aims to reciprocally understand how the interactions of these peptides and proteins alter the underlying membrane properties.