BORDETELLA PERTUSSIS TRACHEAL CYTOTOXIN

博德特氏菌产生的各种毒素和毒力相关因子 百日咳，只有一个已被证明可以复制特定的 百日咳综合征的呼吸道细胞病理学该分子 气管细胞毒素（TCT），一种由 B。百日咳在正常生长期。这个实验室的研究集中在 在分子细节上表征TCT，并将这些研究与 由博德特氏菌属感染引起的疾病状态其他 实验室对TCT样分子（胞壁酰肽）的研究提供了 TCT的作用机制及其在各种生物学中的作用的线索 活动 这一新的赠款支持申请将继续与长期 我们的目标是了解这种毒素是如何导致病理学的， 与百日咳有关。在该项目的三年期间， 将讨论以下两个主要研究问题： I. TCT的分子结构与其生物学特性有何关系？ 功能？酶裂解、化学修饰和肽合成 计划产生TCT结构类似物的多样化集合。 这些分子的详细结构/功能映射将有助于定义 TCT的哪些部分对于毒性和/或 与宿主细胞结合。 二. TCT靶细胞特异性的分子基础是什么？这些 实验将检验TCT与易感宿主结合的假设 细胞通过特定的受体。经典配体-受体结合 细胞培养和器官培养的实验旨在评估 结合特异性，配体结构要求，靶细胞 特异性和结合配体的命运。

Of the various toxins and virulence-related factors produced by Bordetella pertussis, only one has been demonstrated to reproduce the specific respiratory tract cytopathology of the pertussis syndrome. That molecule is tracheal cytotoxin (TCT), a low molecular weight glycopeptide released by B. pertussis during normal growth. This laboratory's research has centered on characterizing TCT in molecular detail and relating those studies to the disease states caused by infections with Bordetella spp. Other laboratories' work on TCT-like molecules (muramyl peptides) has provided clues to TCT's mechanism of action and its role in a variety of biological activities. This application for renewed grant support continues with the long-term goal of understanding how this toxin contributes to the pathology associated with pertussis. During the three-year period of this project, the following two major research questions will be addressed: I. How does the molecular structure of TCT relate to its biological function? Enzymatic cleavage, chemical modification, and peptide synthesis are planned to generate a diverse collection of TCT structural analogs. Detailed structure/function mapping with these molecules will help define what portions of TCT are essential (or unimportant) for toxicity and/or binding to host cells. II. What is the molecular basis for TCT-target cell specificity? These experiments will test the hypothesis that TCT binds to susceptible host cells via a specific receptor. Classical ligand-receptor binding experiments with cell cultures and organ cultures are designed to evaluate binding specificity, ligand structural requirements, target cell specificity, and the fate of bound ligand.