Uncovering the Biophysical Mechanism of Receptor for Advanced Glycation Endproducts Molecular Function

揭示高级糖基化终产物分子功能受体的生物物理机制

• 批准号: 1709099
• 负责人: Emily Smith
• 金额: $ 46.5万
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1709099&HistoricalAwards=false
• 关键词: Uncovering; Biophysical; Mechanism; Receptor; Advanced

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Emily Smith from Iowa State University to investigate the chemical species that allow a class of membrane proteins to function, and to develop a detailed understanding of how the proteins organize and move in a cell membrane. Proteins in the cell membrane have a critical role in how cells get information about their surroundings as well as respond to their environment. One way these proteins function is by moving throughout the cell membrane to facilitate interactions with other proteins and cells. This project is providing information, through optical spectroscopy and microscopy measurements that would advance the understanding of two important membrane proteins associated with many aspects of cellular function. Broader impact activities target middle school, high school, undergraduate and graduate students to meet the societal goals of cultivating a scientifically literate public; increasing the number of students pursuing science degrees including students from underrepresented groups in science; and promoting a strong, diverse and capable scientific workforce to increase America's global competitiveness. These activities are being accomplished in partnership with Science Bound, a pre-college program to increase the number of ethnically diverse Iowa students who pursue science degrees, and the local American Chemical Society SEED program that provides summer research opportunities for economically disadvantaged students.The overarching objective of this work is to measure the clustering, diffusion, and nanoscale organization of a class of cell membrane proteins termed pattern recognition receptors (PRRs). These receptors are part of the innate immune system that recognizes several pathogen-associated molecular patterns and damage-associated molecular patterns. The molecular mechanism of clustering and diffusion within the membrane upon chemically-defined ligand binding events will be measured for two PRRs: receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4). Both PRRs share a subset of ligands, and have been shown to exhibit receptor "cross talk," as evidenced by downstream protein phosphorylation (i.e., signaling). The project is using single particle tracking methods to measure the diffusion of TLR4 and elucidate the role of chemically-characterized ligands in affecting the diffusion of RAGE and TLR4. The RAGE and TLR4 association in the cell membrane is measured by fluorescence resonance energy transfer. Evidence for an association of these two receptors within the membrane has not been reported. It is hypothesized that a direct interaction between RAGE and TLR4 may be an important mechanism of their function, and that diffusion is an important regulator of these interactions. The proposed work is generating a foundation for understanding the molecular biophysical aspects of PRRs' molecular function that will add to the available data on the downstream signaling of these receptors.

凭借该奖项，化学部的生命过程化学项目正在资助爱荷华州立大学的 Emily Smith 博士研究允许一类膜蛋白发挥作用的化学物质，并详细了解蛋白质如何组织并在细胞膜中移动。细胞膜中的蛋白质在细胞如何获取周围环境信息以及对环境做出反应方面发挥着关键作用。这些蛋白质发挥作用的一种方式是穿过细胞膜移动，以促进与其他蛋白质和细胞的相互作用。该项目通过光谱学和显微镜测量提供信息，这将促进对与细胞功能许多方面相关的两种重要膜蛋白的理解。影响更广泛的活动针对初中、高中、本科生和研究生，以实现培养具有科学素养的公众的社会目标；增加攻读科学学位的学生数量，包括来自科学领域代表性不足群体的学生；培养一支强大、多元化和有能力的科学队伍，以提高美国的全球竞争力。这些活这项工作的目的是测量一类称为模式识别受体（PRR）的细胞膜蛋白的聚集、扩散和纳米级组织。 这些受体是先天免疫系统的一部分，可识别多种病原体相关分子模式和损伤相关分子模式。 将针对两种 PRR 测量化学定义的配体结合事件后膜内聚集和扩散的分子机制：晚期糖基化终产物受体 (RAGE) 和 Toll 样受体 4 (TLR4)。 两个 PRR 共享配体子集，并且已被证明表现出受体“串扰”，下游蛋白质磷酸化（即信号传导）证明了这一点。 该项目正在使用单粒子跟踪方法来测量 TLR4 的扩散，并阐明化学特征配体在影响 RAGE 和 TLR4 扩散中的作用。通过荧光共振能量转移来测量细胞膜中的 RAGE 和 TLR4 关联。膜内这两种受体关联的证据尚未报道。据推测，RAGE 和 TLR4 之间的直接相互作用可能是它们功能的重要机制，并且扩散是这些相互作用的重要调节因子。拟议的工作为理解 PRR 分子功能的分子生物物理方面奠定了基础，这将增加有关这些受体下游信号传导的可用数据。

项目成果

Coumarin‐based Fluorescent Probes for Selectively Targeting and Imaging the Endoplasmic Reticulum in Mammalian Cells

• DOI: 10.1111/php.12985
• 发表时间: 2018-08
• 期刊: Photochemistry and Photobiology
• 影响因子: 3.3
• 作者: C. Wijesooriya;Megan Nieszala;Alex Stafford;J. Zimmerman;Emily A. Smith

Direct Photorelease of Alcohols from Boron-Alkylated BODIPY Photocages

• DOI: 10.1021/acs.joc.0c00044
• 发表时间: 2020-04-17
• 期刊: JOURNAL OF ORGANIC CHEMISTRY
• 影响因子: 3.6
• 作者: Peterson, Julie A.;Fischer, Logan J.;Winter, Arthur H.
• 通讯作者: Winter, Arthur H.

Inorganic Semiconductor Quantum Dots as a Saturated Excitation (SAX) Probe for Sub‐Diffraction Imaging

• DOI: 10.1002/cptc.202000195
• 发表时间: 2020-10
• 作者: Ashutosh Kumar Singh;Sadie J. Burkhow;C. Wijesooriya;Brett W. Boote;J. Petrich;Emily A. Smith

The evolution of total internal reflection Raman spectroscopy for the chemical characterization of thin films and interfaces

• DOI: 10.1007/s00216-020-02510-1
• 发表时间: 2020-03
• 期刊: Analytical and Bioanalytical Chemistry
• 影响因子: 4.3
• 作者: C. Nyamekye;J. Bobbitt;Qiaochu Zhu;Emily A. Smith

Efficient Far-Red/Near-IR Absorbing BODIPY Photocages by Blocking Unproductive Conical Intersections

• DOI: 10.1021/jacs.0c07139
• 发表时间: 2020-09-09
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Shrestha, Pradeep;Dissanayake, Komadhie C.;Winter, Arthur H.
• 通讯作者: Winter, Arthur H.