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CAREER: Molecular Recognition of Bacterial Cell Wall Fragments by Yeast and Humans

职业：酵母和人类对细菌细胞壁碎片的分子识别

基本信息

批准号：
1554967
负责人：
Catherine Grimes
金额：
$ 75万
依托单位：
University of Delaware
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1554967&HistoricalAwards=false
关键词：
CAREER Molecular Recognition Bacterial Cell

项目摘要

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Catherine Leimkuhler Grimes from the University of Delaware to investigate the interactions between bacteria, humans and yeast. Bacteria surround themselves with "jackets" called bacterial cell wall to protect themselves from environmental insults. The ultimate goal of this research is to determine how different organisms bind to and are activated by bacterial cell wall fragments leading to an immune response. This information is critical in understanding how a variety of species have solved the problem of binding bacterial cell wall ligands as an initial step in a stimulated response. Using synthetic chemistry, biochemistry, molecular biology and microbiology, the principal investigator is developing a framework of understanding of how bacterial cell wall ligands are recognized across nature. This work ultimately results in a deeper understanding of how three systems; bacterial, human and fungal, function in a common environment. As part of this CAREER award, the principal investigator is developing creative mechanisms for educating students, particularly those from historically underrepresented groups, on how chemists begin to understand the problem of molecular recognition. There are three educational objectives that are integrated with each other, draw inspiration from the problem of sensing bacterial cell walls and are directed at teaching students what it means to be a scientist. The activities involve: (a) partnering with an expert in Early Childhood Education to develop and implement a new curriculum for grades K to 2 focused on how a chemist "senses" phenomena such as light and sound, (b) developing a program to enhance the chemistry background of K to 2 educators, allowing them to more readily approach science concepts when they start their own careers and (c) developing and implementing an introductory biochemistry lab in which undergraduate biochemistry majors use problem-based learning (PBL) to understand how concepts in molecular recognition are used in antibiotics that target the destruction of bacterial cell wall.Organisms from plants to humans take advantage of the strong polymer unique to the bacterial cell wall to recognize the presence of a bacterial cell. However, the molecular details of recognition are not well understood. This project involves the preparation of synthetic analogues of bacterial cell wall to investigate the binding events used by mammalian and fungal systems. The use of these systems allows a comparison of the solutions devised by nature to bind the highly conserved polymer that comprises the cell wall. In two objectives, this research determines the binding events that drive the recognition of bacterial cell wall fragments by innate immune human and fungus receptors. The principal investigator is using chemical synthesis to build modified, tagged versions of bacterial cell wall fragments that are used for the identification and characterization of the binding sites for these molecules and their respective receptors. Bacterial cell wall fragment binding proteins Cyr1p, Nod1 and Nod2, from yeast and humans are being used in the investigation. These proteins are structurally diverse and each has been shown to be stimulated by bacterial cell wall fragments. The principal investigator makes use of a dynamic approach in refining the rules for binding to bacterial cell wall fragments. Student and teachers in K-2 are involved in a new curriculum on chemical sensing and recognition.

有了这个奖项，化学部门的生命过程化学项目将资助特拉华大学的凯瑟琳·莱姆库勒·格莱姆斯博士研究细菌、人类和酵母之间的相互作用。细菌在自己周围包裹着一层叫做细菌细胞壁的“外套”，以保护自己免受环境的侵害。这项研究的最终目的是确定不同的生物体如何结合并被细菌细胞壁碎片激活，从而导致免疫反应。这一信息对于理解不同物种如何将结合细菌细胞壁配体作为刺激反应的第一步来解决问题至关重要。利用合成化学、生物化学、分子生物学和微生物学，首席研究员正在开发一个理解细菌细胞壁配体如何在自然界中被识别的框架。这项工作最终导致更深入地了解三个系统如何；细菌，人类和真菌，在共同的环境中发挥作用。作为这个职业奖的一部分，首席研究员正在开发创造性的机制来教育学生，特别是那些来自历史上代表性不足的群体的学生，让他们了解化学家如何开始理解分子识别的问题。有三个相互结合的教育目标，从感知细菌细胞壁的问题中汲取灵感，并直接教导学生成为一名科学家意味着什么。活动包括：(a)与幼儿教育专家合作，为幼稚园至幼稚园二年级制定和实施一套新课程，重点关注化学家如何“感知”光和声音等现象；(b)制定一项计划，加强幼稚园至幼稚园二年级教育工作者的化学背景；让他们在开始自己的职业生涯时更容易接触到科学概念，以及(c)开发和实施生物化学入门实验室，让生物化学本科专业学生使用基于问题的学习（PBL）来理解分子识别中的概念如何应用于以破坏细菌细胞壁为目标的抗生素。从植物到人类的生物体都利用细菌细胞壁特有的强聚合物来识别细菌细胞的存在。然而，识别的分子细节还没有被很好地理解。该项目包括制备细菌细胞壁的合成类似物，以研究哺乳动物和真菌系统使用的结合事件。使用这些系统可以比较自然设计的溶液来结合构成细胞壁的高度保守的聚合物。在两个目标中，本研究确定了驱动先天免疫人类和真菌受体识别细菌细胞壁片段的结合事件。首席研究员正在使用化学合成来构建修饰的、标记的细菌细胞壁片段，用于识别和表征这些分子及其各自受体的结合位点。来自酵母和人类的细菌细胞壁片段结合蛋白Cyr1p、Nod1和Nod2被用于研究。这些蛋白质在结构上是多种多样的，每一种都被细菌细胞壁碎片所刺激。首席研究员利用一种动态的方法来完善与细菌细胞壁碎片结合的规则。在K-2的学生和教师参与化学传感和识别的新课程。