GENE KNOCK-OUT MICE AS MODELS FOR THE LEPROSY SPECTRUM

描述(由申请人提供)：建议的研究将探索 基因敲除(KO)小鼠的麻风分支杆菌足垫感染 精心挑选，因为它们破坏了在宿主中起关键作用的基因 对分支杆菌病原体的细胞免疫(CMI)。麻风杆菌在日本的生长 将监测足垫和形成的实验性肉芽肿 将被分析以确定这些KO小鼠品系是否可以作为 CMI的关键免疫调节元件导致独特的 人类麻风的免疫病理谱系。CMI的回应将进一步 条件性敲除额外基因产物在KO小鼠中的修饰 在感染麻风杆菌之前或之后或通过选择性地恢复某些 感染后基因功能中断。KO小鼠模型的建立 人类麻风谱的离散因素应开放调查 边界地区固有的不稳定性背后的机制 降级和升级转向麻风病和 对于谱型中的类结核末端，人们知之甚少。更多 重要的是，KO小鼠麻风模型和额外的操作 这些提出的模型可能会为深入了解这种机制提供帮助。 对第一型和第二型反应的突然发生负责。最终， 这一基本知识可以预测和预防这些毁灭性的 反应，这明显加剧了神经损伤。 许多关于结核分枝杆菌在基因KO小鼠中的研究已经被报道。我们 建议麻风杆菌-KO小鼠研究将允许更详细的解剖 CMI的作用机制。有针对性地移除一些分离的基因功能 通常会极大地加剧实验性小鼠结核病，可能是通过 压倒寄主抗性中的某些补偿机制。在标记中 相比之下，麻风杆菌是一种安静的、适应良好的、专性的细胞内病原体。 这一建议是基于其速度慢的特点的可能性 生长、低毒力和慢性致病正是它们的属性 将使在靶基因KO小鼠中研究麻风杆菌成为一种理想的模型 寄主CMI的主要冗余和补偿机制分析 对一般感染和细胞内分枝杆菌病原体的抵抗力 尤其是。

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.