PEPTIDES ACTIVE AGAINST INTRACELLULAR PATHOGENIC DISEASE

描述：细胞内细菌负责广泛的 人类的慢性和致命疾病，包括肺结核和波浪形 发热（布鲁氏菌病），由结核分枝杆菌引起， 流产布鲁氏菌。这些细菌很难 需要肺部抗生素治疗，因为它们 隐藏了宿主巨噬细胞的信息对于其中许多感染，甚至 症状消除后， 通常留在巨噬细胞聚集体中，称为肉芽肿。这 残余感染通常是无害的，但会导致复发 感染，这往往导致死亡的免疫组成 如艾滋病患者。拟议研究的目的是 探索治疗细胞内致病性疾病的新机制 通过螺旋状两亲分子选择性溶解受感染的巨噬细胞 缩氨酸这项工作中的新肽含有大百分比的 非天然的α分布氨基酸，这使得它们高度 螺旋的，即使它们相对较短（10个氨基酸）。主要 假设这些肽选择性地破坏感染的巨噬细胞， 与细胞内的病原体接触， 保护性生态位，从而使它们更容易受到添加的抗生素的影响 和免疫反应。 这部小说的机制和范围间接 抗微生物活性以及肽结构要求 负责观察到的选择性将根据 具体目的：（1）探讨多肽诱导的细胞凋亡机制， 体外裂解易感巨噬细胞。显微镜实验使用 标记的细菌和肽将确定最佳浓度 感染的巨噬细胞的选择性裂解以及肽的浓度 结合并溶解巨噬细胞。(2)确定最活跃的 以及用于体外和体内的选择性肽或肽模拟物 活动从目前已知的最具活性的肽开始， 肽的结构和大小将变化以确定需要什么 以获得最佳的活性和选择性裂解感染的巨噬细胞。 (3)多个肽剂量的优化和可能的协同作用 肽与抗生素对牛种布氏杆菌的作用， 离体和体内结核分枝杆菌。多个肽剂量 将使用感染的细菌离体研究添加和不添加抗生素的情况。 肉芽肿和体内使用建立的小鼠模型系统。

DESCRIPTION: Intracellular bacteria are responsible for a wide range of chronic and lethal disease in man including tuberculosis and undulant fever (brucellosis), which are caused by Mycobacterium tuberculosis and Brucella abortus, respectively. These bacteria are difficult for the immune system to kill and require lung antibiotic treatment because they hide insight the host's macrophages. For many of these infections, even after disease symptoms have been eliminated, residual live bacteria are often left in macrophage conglomerations known as granulomas. This residual infection is normally harmless, but is responsible for recurrence of infection, which often results in death for immuno-comprised individuals such as those with AIDS. The purpose of the proposed study is to explore a new mechanism for treating intracellular pathogenic diseases by selective lysis of infected macrophages by helical amphipathic peptides. The novel peptides in this work contain large percentages of unnatural alpha, alpha-distributed amino acids, which makes them highly helical even when they are relatively short (10 amino acids). The main hypothesis is that these peptides selectively destroy macrophages infected with intracellular pathogens, releasing the pathogens from their protective niche, thus making them more vulnerable to added antibiotics and the immune response. The mechanism and scope of this novel indirect antimicrobial activity as well as the peptide structural requirements responsible for the observed selectivity will be examined according the following Specific Aims: (1) To probe the mechanism of peptide induced lysis of susceptible macrophage in vitro. Microscopy experiments using labeled bacteria and peptides will determine optimal concentration for selective lysis of infected macrophages and at what concentration peptides bind to and lyse the macrophages. (2) Identification of the most active and selective peptide or peptide mimetic for in vitro and in vivo activity. Starting with the most active peptides currently known the peptide structure and size will be varied to determine what is required for optimal activity and selectivity in lysing of infected macrophages. (3) Optimization of multiple peptide doses and possible synergistic effects of peptides with antibiotics against Brucella abortus and Mycobacterium tuberculosis ex vivo and in vivo. Multiple peptides doses with and without added antibiotics will be studied ex vivo using infected granulomas and in vivo using established mouse model systems.