Uncovering Biophysical Mechanisms of Crosstalk in Pattern Recognition Receptors

揭示模式识别受体串扰的生物物理机制

• 批准号: 2003308
• 负责人: Emily Smith
• 金额: $ 49.87万
• 依托单位: Iowa State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2003308&HistoricalAwards=false
• 关键词: Uncovering; Biophysical; Mechanisms; Crosstalk; Pattern

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.

通过该奖项，《生命过程》计划的化学计划是为爱荷华州立大学的艾米丽·史密斯（Emily Smith）教授提供资金，以揭示涉及受体聚类和模式识别受体（PRRS）中受体聚类和扩散的膜蛋白串扰的机制。当细胞遇到外部生物体和其他入侵者时，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到入侵者，而且还控制细胞如何产生反应。 免疫反应必须非常仔细地平衡，以与外部入侵者作斗争，同时又不会产生广泛的炎症，这本身就是有害的。 艾米丽·史密斯（Emily Smith）教授及其在爱荷华州立大学的研究小组正在使用光学显微镜研究两种重要的膜蛋白参与这种免疫反应，并回答了这两种膜蛋白如何共同起作用的关键问题，以产生对化学响应的反应。特征是入侵物种。一系列综合活动为来自低收入家庭的高中学生以及研究与科学政策的本科和研究生培训提供了宣传。这些活动的总体目标是授予追求杰出科学所必需的技能，同时获得蛋白质化学和生物物理测量科学方面的专业技能。该项目涉及膜蛋白质串扰和聚类和相关模式的最先进的生物物理研究具有免疫反应。这项工作重点的两个受体是晚期糖基化最终产物（RAGE）和TOLL样受体4（TLR4）的受体。在存在含有损伤相关分子模式（抑制剂）和病原体相关分子模式（PAMP）的异质化配体的情况下，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受体时，串扰会产生。众所周知，RAGE和TLR4共享常见的配体和信号通路，但是他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特征化的配体研究受体的愤怒异构体和差异化磷酸化形式。通过单分子定位显微镜和单个粒子跟踪，正在测量受体纳米级组织和扩散。研究目标与推进来自低收入家庭的高中学生的科学素养以及培训化学物理学和数据驱动科学政策的本科生和研究生的教育目标。使用基金会的知识分子优点和更广泛的审查标准，被认为值得通过评估来支持。