Uncovering Biophysical Mechanisms of Crosstalk in Pattern Recognition Receptors

通过这一奖项，生命过程化学项目资助了爱荷华州立大学的Emily Smith教授，以揭示涉及模式识别受体（PRRs）中受体聚集和扩散的膜蛋白串扰机制。当细胞遇到外来生物和其他入侵者时，必须产生免疫反应。对免疫反应至关重要的是细胞膜中的蛋白质。这些膜蛋白不仅检测入侵者，而且还控制细胞如何产生反应。免疫反应必须非常小心地平衡，以对抗外部入侵者，同时不产生广泛的炎症，这本身就是有害的。爱荷华州立大学的艾米丽·史密斯教授和她的研究小组正在使用光学显微镜研究两种重要的膜蛋白在这种免疫反应中的作用，并回答这两种膜蛋白如何共同作用以产生对化学特征入侵物种的反应的关键问题。一系列综合活动向来自低收入家庭的高中生提供外展服务，并为本科生和研究生提供研究和科学政策方面的培训。这些活动的总体目标是传授必要的技能，以追求卓越的科学，同时获得蛋白质化学和生物物理测量科学的专业技能。该项目涉及与免疫反应相关的膜蛋白串扰和聚集和扩散模式的最先进的生物物理研究。这两种受体是本研究的重点，即晚期糖基化终产物受体（RAGE）和toll样受体4 （TLR4）。在含有损伤相关分子模式（DAMPs）和病原体相关分子模式（PAMPs）的异质不同配体存在的情况下，这两种受体都是炎症反应的一部分。当一个受体的功能影响另一个受体时，就会产生串扰。已知RAGE和TLR4具有共同的配体和信号通路，但对它们串扰的细节知之甚少。这项工作的一个重要方面是使用化学表征配体来研究RAGE异构体和受体的差异磷酸化形式。用单分子定位显微镜和单粒子跟踪技术测量了受体纳米级的组织和扩散。研究目标与提高低收入家庭高中生的科学素养、培养化学物理和数据驱动科学政策的本科生和研究生的教育目标相结合。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, the Chemistry of Life Processes Program is funding Professor Emily Smith at Iowa State University to reveal mechanisms of membrane protein crosstalk that involve receptor clustering and diffusion in pattern recognition receptors (PRRs). Cells must produce an immune response when they encounter outside organisms and other invaders. Critical to the immune response are proteins in the cell membrane. These membrane proteins not only detect the invader, but they also control how the cell produces a response. The immune response must be very carefully balanced to fight the outside invader while not producing extensive inflammation, which is itself harmful. Professor Emily Smith and her research group at Iowa State University are using optical microscopy to study the involvement of two important membrane proteins in this immune response, and to answer the critical question of how these two membrane proteins work together to generate a response to chemically-characterized invading species. A set of integrated activities provides outreach to high school students from low-income families, as well as undergraduate and graduate student training in research and science policy. The overarching goal of these activities is to impart the skills necessary to pursue outstanding science while acquiring specialized skills in protein chemistry and biophysical measurement science.This project involves state-of-the-art biophysical studies of membrane protein crosstalk and clustering and diffusion patterns associated with the immune response. The two receptors that are the focus of this work are the Receptor for Advanced Glycation Endproducts (RAGE) and Toll-like Receptor 4 (TLR4). Both receptors are part of the inflammatory response in the presence of heterogeneously diverse ligands containing damage associated molecule patterns (DAMPs) and pathogen associated molecular patterns (PAMPs). Crosstalk results when the function of one receptor influences the other receptor. RAGE and TLR4 are known to share common ligands and signaling pathways, but the details of their crosstalk are poorly understood. An important aspect of this work is the use of chemically-characterized ligands to study RAGE isomers and differentially phosphorylated forms of the receptor. Receptor nanoscale organization and diffusion are being measured with single molecule localization microscopy and single particle tracking. The research objectives are integrated with the educational objectives of advancing the scientific literacy of high school students from low-income families, as well as training undergraduate and graduate students in chemical physics and data-driven science policy.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.