GENE KNOCK-OUT MICE AS MODELS FOR THE LEPROSY SPECTRUM

描述（由申请方提供）：拟定研究将探索 敲除（KO）小鼠品系中麻风分枝杆菌足垫感染 精心挑选，因为它们破坏了在宿主中起关键作用的基因， 对分枝杆菌病原体的细胞介导免疫（CMI）。微囊藻生长麻风病 脚垫将被监测， 将进行分析，以确定这些KO小鼠品系是否可以作为模型， CMI的关键免疫调节元件，导致独特的 人类麻风免疫病理谱。CMI的回应将进一步 在KO小鼠中通过条件性敲除额外的基因产物进行修饰 感染M.或者通过选择性地恢复某些 感染后基因功能被破坏。KO小鼠模型的开发 人类麻风病谱的离散元素应开放调查， 边界地区所固有的不稳定性的内在机制， 在这个范围内，降级和升级转向麻风瘤， 结核病谱的两端，分别是知之甚少。更 重要的是，麻风病的KO小鼠模型和麻风病的额外操作， 这些模型的提出，可能提供深入了解的机制， 导致1型和2型反应的突然发作。最后， 这些基本知识可以预测和预防这些破坏性的 反应，这显着增强神经损伤。 许多研究报道了M。基因敲除小鼠中的结核病。我们 建议M.麻风-KO小鼠研究将允许更详细的解剖 CMI的机制。靶向去除一些孤立的基因功能 通常会大大加剧实验性鼠结核病，也许是因为 压倒了宿主抵抗力的某些补偿机制。形成鲜明 对比，M.麻风是一种安静的、适应良好的、专性细胞内病原体。 这一建议是基于可能性，其特点是速度慢 生长、低毒力和慢性致病性是 将使M.麻风在靶基因敲除小鼠中是理想的模型 分析了CMI在宿主体内的主要冗余和补偿机制 对一般感染和细胞内分枝杆菌病原体的抗性 特别是。

DESCRIPTION (provided by the applicant): The proposed studies will explore Mycobacterium leprae foot pad infection in knockout (KO) mouse strains carefully selected for their disruption in genes that play key roles in host cell mediated immunity (CMI) to mycobacterial pathogens. Growth of M. leprae in the foot pad will be monitored and the experimental granulomas which develop will be analyzed to determine if these KO mouse strains can serve as models for the key immunoregulatory elements of CMI that result in the unique immunopathological spectrum of human leprosy. CMI responses will be further modified in the KO mice by conditionally knocking-out additional gene products before or after infection with M. leprae or by selectively restoring certain disrupted gene functions after infection. Development of KO mouse models for discrete elements of the human leprosy spectrum should open investigation into the mechanisms underlying the instability inherent to the borderline area of this spectrum where downgrading and upgrading shifts toward the lepromatous and tuberculoid ends of the spectrum, respectively, are poorly understood. More importantly, KO mouse models of leprosy and the additional manipulations of these models that are proposed may afford insight into the mechanisms responsible for the abrupt onset of type 1 and type 2 reactions. Ultimately, this basic knowledge may permit prediction and prevention of these devastating reactions, which markedly enhance nerve damage. Numerous studies have been reported with M. tuberculosis in gene KO mice. We suggest that M. leprae-KO mouse studies will permit more detailed dissection of the mechanisms of CMI. Targeted removal of a number of isolated gene functions often greatly exacerbates experimental murine tuberculosis, perhaps by overwhelming certain compensatory mechanisms in host resistance. In marked contrast, M. leprae is a quiet, well adapted, obligate intracellular pathogen. This proposal is based on the likelihood that its characteristics of slow rate of growth, low virulence and chronic pathogenesis are the very attributes which will make the study of M. leprae in targeted gene KO mice an ideal model for analyzing the principal redundant and compensatory mechanisms of CMI in host resistance to infection in general and to intracellular mycobacterial pathogens in particular.