MYCOBACTERIUM LEPRAE ANTIGENS AND NERVE DAMAGE

麻风分枝杆菌抗原与神经损伤

• 批准号: 6612992
• 负责人: ANURA RAMBUKKANA
• 金额: $ 25.39万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612992
• 关键词: Mycobacterium leprae; Schwann cells; bacteria infection mechanism; bacterial antigens; binding proteins; glycolipids; laminin; molecular cloning; molecular pathology; myelinopathy; nerve injury; plasmids; protein binding; tissue /cell culture

DESCRIPTION (Adapted from the Applicant's Abstract): Mycobacterium leprae is unique among bacterial pathogens in its ability to invade the peripheral nervous system and to cause nerve damage, which accounts for the disabilities in leprosy patients. This property makes M. leprae a model to study the mechanism of nerve damage, particularly demyelination, in other neurodegenerative diseases. The components of M. leprae which bind peripheral nerves and induce nerve damage are not known. The PI proposes that M. leprae interferes with critical Schwann cell functions and subsequently causes nerve dysfunction before the immune response comes into play. Using a well-characterized in vitro Schwann cell-sensory neuron co-culture system, which mimics in vivo conditions, but is devoid of immune cells, the PI found that M. leprae and its cell wall fraction alone induce significant demyelination and axonal damage. The PI and colleagues have recently shown that laminin-2 is an initial neural target of M. leprae; since the laminin-2 isoform completely surrounds the Schwann cell-axon units, the PI proposes that M. leprae should bind to laminin-2 before inducing nerve damage in early infection. Therefore, laminin-2-binding antigens are the most likely components of M. leprae that mediate bacterial binding and invasion, and also induce nerve damage. The main theme of the application is to systematically identify the laminin-binding components of M. leprae that mediate the initial interaction with peripheral nerves and characterize their capacity to induce nerve damage. In preliminary studies, the PI has shown that phenolic glycolipid 1 (PGL-1) and a novel M. leprae cell wall protein of 21 kDa bind laminin-2. These data also suggest the presence of other laminin-binding components of M. leprae. Since the preliminary studies indicate that PGL-1 alone can induce significant demyelination, the PI proposes that the laminin-binding components are capable of inducing demyelination. Therefore, the PI proposes the following: (1) characterize the laminin-2-binding activity of PGL-1 and the 21 kDa protein and their roles in Schwann cell invasion, (2) identify and characterize other potential laminin-binding components in the M. leprae genome with special emphasis on M. leprae-specific proteins by screening an ordered cosmid library of M. leprae, using laminin-2 as a probe, and (3) characterize the demyelination and axonal damage induced by M. leprae laminin-binding components. These studies should provide important insights into the early molecular events of nerve damage in leprosy and other neurodegenerative diseases and will eventually lead to the development of novel therapeutics and diagnostics for peripheral neuropathies.

描述（改编自申请人的摘要）：麻风分枝杆菌是 在细菌病原体中，其独特之处在于其侵入外周的能力， 神经系统，并造成神经损伤，这占残疾 在麻风病人身上。这个属性使M。麻风病的一个模型， 神经损伤的机制，特别是脱髓鞘，在其他 神经退行性疾病M.麻风病结合外周 神经和诱发神经损伤是未知的。PI建议M.麻风 干扰关键的雪旺细胞功能， 在免疫反应开始发挥作用之前就出现功能障碍。使用 良好表征的体外雪旺细胞-感觉神经元共培养系统， PI发现， 分枝麻风及其细胞壁部分单独诱导显著的 脱髓鞘和轴突损伤。PI及其同事最近表明， 层粘连蛋白-2是M.麻风;由于层粘连蛋白-2亚型 完全包围了许旺细胞轴突单位，PI提出M。 麻风在早期诱导神经损伤之前应与层粘连蛋白-2结合 感染因此，层粘连蛋白-2结合抗原是最可能的组分 分枝介导细菌结合和侵入并诱导神经 损害申请的主题是系统地识别 层粘连蛋白结合组分。介导初始相互作用的麻风 与周围神经，并表征其诱导神经损伤的能力。 在初步研究中，PI已经表明酚糖脂1（PGL-1）和 小说M 21 kDa麻风细胞壁蛋白结合层粘连蛋白-2。这些数据还 提示存在M的其他层粘连蛋白结合组分。麻风病人以来 初步研究表明PGL-1单独可诱导显著的 脱髓鞘，PI提出层粘连蛋白结合成分能够 导致脱髓鞘因此，PI提出以下建议：（1） 表征PGL-1和21 kDa蛋白的层粘连蛋白-2结合活性， 它们在雪旺细胞侵袭中的作用，（2）识别和表征其他 M.麻风病基因组具有特殊 强调M。麻风特异性蛋白质的有序粘粒文库筛选 分枝麻风，使用层粘连蛋白-2作为探针，和（3）表征 M.麻风层粘连蛋白结合 件.这些研究应该提供重要的见解， 麻风和其他神经退行性疾病中神经损伤的分子事件 疾病，并最终导致新的治疗方法的发展， 周围神经病变的诊断。