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Quantitative Label-Free Investigations of Biorecognition

生物识别的定量无标记研究

基本信息

批准号：
1904424
负责人：
Joel Harris
金额：
$ 49.35万
依托单位：
University of Utah
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1904424&HistoricalAwards=false
关键词：
Quantitative Label Free Investigations Biorecognition

项目摘要

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Joel Harris and his research group at the University of Utah are developing a new microscopy technique to investigate the mechanisms of reactions involving biological molecules employed in therapeutic applications and clinical diagnostics. The measurements are carried out on surfaces that mimic the structure of cell membranes, so that the response can be related to the action of these molecules in biologically- and clinically-relevant systems. In most investigations of this type, emission of light from a dye label is used to monitor the reactions of the biological molecules of interest. In some instances the dye label can interfere with the interactions of interest. The approach being developed by the Harris group avoids the need for the label, and therefore the associated complications. The fundamental information derived from these investigations should advance understanding and development of new biologically-derived pharmaceuticals (biologics) and more selective clinical diagnostic assays. The group is also extending the tools to studies related to cultural heritage science, and communicating the science to a broad audience through outreach to a local fine arts museum. The program is training graduate students, undergraduates, and postdoctoral associates in microscopy and bioanalytical chemistry, topics that are relevant to advancing U.S. science and technology. Additional science education and outreach comes through development of Chemistry-under-the-Microscope exercises in undergraduate chemistry labs.The measurement innovation in this project is the application of confocal-Raman microscopy to measure biorecognition reactions within individual porous particles modified with lipid bilayers. Raman spectroscopy is a label-free method that can report the structure and interactions of proteins. A major limitation of Raman is the low sensitivity resulting from small scattering cross sections. In this work, this limitation is overcome by enhancing the surface area that can be interrogated within a small detection volume through use of porous silica particle supports. The internal surfaces of these particles are modified with lipid bilayers and used as substrates for investigating biorecognition reactions relevant to protein-lipid interactions and bioassay applications. With calibration using internal standards, confocal Raman microscopy can provide both structural information and assessment of absolute surface coverages for biomolecules involved in interfacial reactions. This research is generating new understanding of biomolecule association, stoichiometry, and structure that govern peptide-lipid membrane interactions and protein biorecognition.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.

在化学系化学测量和成像项目的支持下，乔尔·哈里斯教授和他在犹他大学的研究小组正在开发一种新的显微镜技术，以研究涉及治疗应用和临床诊断中生物分子的反应机制。测量是在模拟细胞膜结构的表面上进行的，因此响应可以与这些分子在生物和临床相关系统中的作用相关。在大多数此类研究中，染料标记的发光用于监测感兴趣的生物分子的反应。在某些情况下，染料标记可能会干扰感兴趣的相互作用。哈里斯小组正在开发的方法避免了对标签的需要，从而避免了相关的并发症。从这些研究中获得的基本信息应能促进对新的生物衍生药物（生物制剂）和更具选择性的临床诊断测定的理解和开发。该小组还将这些工具扩展到与文化遗产科学相关的研究，并通过当地美术博物馆向广大观众传播科学。该项目正在对显微镜和生物分析化学领域的研究生、本科生和博士后进行培训，这些主题与推进美国科学技术相关。额外的科学教育和推广是通过在本科生化学实验室开展显微镜下化学练习来实现的。该项目的测量创新是应用共焦拉曼显微镜来测量脂质双层修饰的单个多孔颗粒内的生物识别反应。拉曼光谱是一种无标记方法，可以报告蛋白质的结构和相互作用。拉曼的一个主要限制是由于散射截面小而导致灵敏度低。在这项工作中，通过使用多孔二氧化硅颗粒支撑物来增强可在小检测体积内进行询问的表面积，从而克服了这一限制。这些颗粒的内表面用脂质双层进行修饰，并用作研究与蛋白质-脂质相互作用和生物测定应用相关的生物识别反应的底物。通过使用内标进行校准，共焦拉曼显微镜可以提供结构信息并评估参与界面反应的生物分子的绝对表面覆盖度。这项研究正在对控制肽-脂质膜相互作用和蛋白质生物识别的生物分子关联、化学计量和结构产生新的理解。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。