Epithelial mechanisms of inducible resistance to AML-associated pneumonia

项目总结 肺炎是急性髓系白血病(AML)患者的主要死亡原因。尽管不变 将巨大的脆弱组织表面积暴露在外部环境中，这是肺部固有的 在确定感染之前，防御系统会清除大多数吸入和吸入的病原体。这些相同的粘膜 防御可以使用一种新型的吸入疗法来治疗刺激，该疗法由非直觉的通行费组成- 类受体(TLR)激动剂组合。这种可诱导的耐药性与快速的肺内相关。 杀死病原体并防止小鼠因常见的AML引起的致命性肺炎而死亡- 相关病原体，即使在严重化疗导致免疫损害的情况下也是如此。这个 肺上皮细胞是可诱导反应的主要效应者的发现使这一方法 尤其适用于中性粒细胞减少的急性髓系白血病患者。这个应用程序提出要剖析分子 这一显着现象背后的机制，以帮助临床翻译这项技术，用于 并促进对新的宿主-病原体相互作用的了解。 目标1将确定对急性髓细胞白血病相关的诱导耐药所需的肺上皮细胞群 肺炎。捐款将通过比较急性髓系白血病病原体的诱导性杀伤和初级 通过对小鼠细胞和人类上皮细胞的功能测试，选择性地缺失TLR信号。 目标2将确定白血病细胞或标准药物治疗是否会削弱可诱导的耐药性 细胞毒性或低甲基化AML方案。这将在体内和体外进行评估，基于对 生存、病原体杀灭、上皮活力、细胞激活、抗菌效应物和循环白细胞 目标3将剖析诱导抗性的分子机制，以确定保护是否可以 尽管联合应用了现代靶向分子AML治疗，但仍在继续，并促进发现 新的上皮刺激物。小鼠的遗传操作和体外模型将识别所需的信号和 并有望提供对观察到的不明原因的TLR协同作用的洞察。 拟议的研究有望确定关键细胞、信号通路和效应分子。 可诱导抗性，促进发现更有效的抗性诱导剂，探索意想不到的TLR 相互作用，评估诱导耐药与AML及其治疗的相互作用，鉴定AML人群 最有可能从治疗中受益，并促进这项技术迅速转化为临床，因此 急性髓细胞白血病患者可以在易受感染的高峰期得到保护，免受致命肺炎的侵袭。

PROJECT SUMMARY Pneumonia is the leading cause of death among patients with acute myeloid leukemia (AML). Despite constant exposure of an immense surface area of delicate tissue to the external environment, the lungs' intrinsic defenses clear most aspirated and inhaled pathogens before infections are established. These same mucosal defenses can be therapeutically stimulated using a novel inhalational therapy comprised of a non-intuitive Toll- like receptor (TLR) agonist combination. This inducible resistance is associated with rapid intrapulmonary pathogen killing and prevents death in mice from otherwise lethal pneumonias caused by common AML- associated pathogens, even in the setting of severe chemotherapy-induced immunocompromise. The discovery that lung epithelial cells are principle effectors of the inducible response makes this approach particularly appealing for use in neutropenic AML patients. This application proposes to dissect the molecular mechanisms underlying this remarkable phenomenon to aid clinical translation of this technology for use in AML patients and to advance understanding of novel host-pathogen interactions. Aim 1 will identify the lung epithelial cell populations required for inducible resistance against AML-associated pneumonia. Contributions will be established by comparing inducible killing of AML pathogens by primary mouse and human epithelial cells and by functional testing of mice cell-selectively deficient in TLR signaling. Aim 2 will determine whether inducible resistance is impaired by leukemia cells or by treatment with standard cytotoxic or hypomethylating AML regimens. This will be assessed in vivo and in vitro based on effects on survival, pathogen killing, epithelial vitality, cellular activation, antimicrobial effectors, and circulating leukocytes Aim 3 will dissect the molecular mechanisms of inducible resistance to determine whether protection can persist despite co-administration of modern targeted molecular AML treatments, and to facilitate discovery of novel epithelial stimuli. Mouse genetic manipulation and in vitro models will identify required signaling and effector molecules and are expected to provide insight into the unexplained TLR synergy observed. The proposed studies are expected to identify critical cells, signaling pathways, and effector molecules of inducible resistance, promote discovery of more efficacious inducers of resistance, explore unanticipated TLR interactions, assess interactions of inducible resistance with AML and its treatments, identify AML populations most likely to benefit from the treatment, and facilitate the rapid translation of this technology into the clinic, so that AML patients can be protected from lethal pneumonia during periods of peak vulnerability.