Uncovering Biophysical Mechanisms of Crosstalk in Pattern Recognition Receptors

有了这个奖项，生命过程计划的化学资助艾米丽史密斯教授在爱荷华州州立大学，以揭示膜蛋白串扰的机制，涉及受体聚集和扩散的模式识别受体（PRR）。当细胞遇到外部生物和其他入侵者时，它们必须产生免疫反应。免疫反应的关键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，这本身是有害的。 爱荷华州州立大学的艾米丽Smith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参与，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联服务，并对本科生和研究生进行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，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。该项目涉及膜蛋白质串扰和与免疫反应相关的聚集和扩散模式的最先进的生物物理研究。这项工作的重点是两种受体，即晚期糖基化终产物受体（Receptor for Advanced Glycation Endproducts，TLR）和Toll样受体4（Toll样受体4，TLR4）。两种受体都是在含有损伤相关分子模式（DAMP）和病原体相关分子模式（PAMP）的异质多样配体存在下炎症反应的一部分。当一个受体的功能影响另一个受体时，就会产生串扰。已知TLR4和TLR4共享共同的配体和信号通路，但对它们的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的配体来研究受体的异构体和差异磷酸化形式。受体纳米级组织和扩散正在测量单分子定位显微镜和单粒子跟踪。该奖项的研究目标与教育目标相结合，即提高低收入家庭高中生的科学素养，以及培养本科生和研究生的化学物理和数据驱动的科学政策。该奖项反映了NSF的法定使命，并通过使用基金会的智力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.