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.

有了这个奖项，化学部的生命过程化学计划正在资助爱荷华州州立大学的艾米丽史密斯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在细胞膜中组织和移动。细胞膜中的蛋白质在细胞如何获得有关其周围环境的信息以及对环境做出反应方面起着关键作用。这些蛋白质的功能之一是通过在细胞膜上移动，以促进与其他蛋白质和细胞的相互作用。该项目通过光学光谱和显微镜测量提供信息，这将促进对与细胞功能的许多方面相关的两种重要膜蛋白的理解。更广泛的影响活动针对初中、高中、本科和研究生，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人数，包括来自科学领域代表性不足群体的学生;促进强大、多样化和有能力的科学工作队伍，以提高美国的全球竞争力。这些活动是与Science Bound合作完成的，Science Bound是一个大学预科项目，旨在增加追求科学学位的种族多样性爱荷华州学生的数量，当地的美国化学学会SEED项目为经济困难的学生提供夏季研究机会。这项工作的首要目标是测量集群，扩散，和称为模式识别受体（PRRs）的一类细胞膜蛋白的纳米级组织。 这些受体是先天免疫系统的一部分，其识别几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（EGFR）和Toll样受体4（TLR 4）。 两种PRR共享配体的子集，并且已经显示出表现出受体“串扰”，如通过下游蛋白磷酸化（即，信令）。 该项目使用单粒子跟踪方法来测量TLR 4的扩散，并阐明化学表征的配体在影响TLR 4和TLR 4扩散中的作用。通过荧光共振能量转移测量细胞膜中的TLR和TLR 4缔合。这两种受体在膜内的关联的证据尚未报道。据推测，直接之间的相互作用，TLR 4和TLR 4可能是它们的功能的一个重要机制，扩散是这些相互作用的一个重要调节器。拟议的工作正在为理解PRR分子功能的分子生物物理方面奠定基础，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

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.

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