STRUCTURE OF LAM IN RELATION TO BIOLOGY AND BIOSYNTHESIS

LAM 结构与生物学和生物合成的关系

• 批准号: 2672427
• 负责人: DELPHI CHATTERJEE
• 金额: $ 17.18万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672427
• 关键词: Mycobacterium tuberculosis; T lymphocyte; bacterial antigens; carbohydrate biosynthesis; carbohydrate structure; cell wall; cellular immunity; chemical structure function; cytokine; drug resistance; epitope mapping; genetic strain; laboratory mouse; leprosy; mannans; monoclonal antibody; surface antigens; tuberculosis; virulence

DESCRIPTION (Adapted from applicant's abstract): The re-emergence of tuberculosis as a public health problem has been complicated by the lack of effective chemotherapeutic agents and the development of drug resistant strains. The cell wall of its causative agent, Mycobacterium tuberculosis, is known to be the target of some of the most effective antimycobacterial drugs including ethambutol which is known to inhibit the biosynthesis of the arabinan of the cell wall proper and the associated lipoarabinomannan (LAM). A diverse range of biological studies over the past few years has collectively provided compelling evidence implicating LAM as a key surface molecule in host-pathogen interactions. The production of truncated LAM variants by cell wall mutants defective in LAM biosynthesis as a consequence of ethambutol resistance provides invaluable model compounds for both structural and functional studies aiming at defining the relevance of LAM in pathogenesis. Specifically, the fine details of the arabinan assembly and its attachment to the phosphatidylinositol mannan core will be characterized and structural motifs positively correlating with particular biological attributes of clinical isolates will be identified. Tailor-made synthetic oligosaccharide probes and well defined monoclonal antibodies will be generated for structural, biosynthesis, and genetic studies of LAM, as well as to define its situation and orientation within the cell wall framework of viable bacilli. CD1 restricted recognition of LAM by T cells will be examined in the context of cell mediated immunity in both tuberculosis and leprosy and its concomitant induction of cytokine secretion. Chemically and/or enzymatically modified arabinan and mannan will be derived from LAM for detailed structural analysis and further used to delineate specific epitopes of LAM recognized by T cells. Thus, the unifying theme of this Research Proposal is the structural analysis and manipulation of LAM, supplemented by other synthetic probes and monoclonal antibodies to be generated, to define its primary structure, conformation and ultracellular location, in relation to its biosynthesis and biology.

描述（改编自申请人摘要）： 结核病作为一个公共卫生问题，由于缺乏 有效的化疗药物和耐药的发展 菌株 它的病原体，结核分枝杆菌的细胞壁， 已知是一些最有效的抗分枝杆菌药物的靶点 包括乙胺丁醇在内的药物，已知乙胺丁醇可抑制 细胞壁的阿拉伯聚糖和相关的脂阿拉伯甘露聚糖（LAM）。 在过去的几年里，各种各样的生物学研究 共同提供了令人信服的证据，表明LAM是一个关键表面， 分子在宿主-病原体相互作用中的作用 截短LAM的产生 由于细胞壁突变体导致LAM生物合成缺陷， 对乙胺丁醇耐药性的研究提供了宝贵的模型化合物， 结构和功能研究，旨在确定LAM的相关性， 发病机制 具体来说，阿拉伯大会及其附件的细节 磷脂酰肌醇甘露聚糖核心的特征和结构 与特定生物学属性正相关的基序 将鉴定临床分离株。 定制合成低聚糖 将产生探针和明确的单克隆抗体， LAM的结构、生物合成和遗传研究，以及定义 它在细胞壁框架内的位置和方向 杆菌。 T细胞对LAM的CD 1限制性识别将在以下研究中进行检查： 结核病和麻风病中细胞介导免疫的背景， 其伴随的细胞因子分泌的诱导。 化学和/或 酶改性的阿拉伯聚糖和甘露聚糖将衍生自LAM， 详细的结构分析，并进一步用于描绘特定的表位 T细胞识别的LAM。 因此，本研究的统一主题 建议是LAM的结构分析和操作， 其他合成探针和单克隆抗体，以确定 它的一级结构、构象和超细胞位置， 它的生物合成和生物学。