Epithelial mechanisms of inducible resistance to AML-associated pneumonia

诱导耐药 AML 相关肺炎的上皮机制

• 批准号: 8628224
• 负责人: Scott E. Evans
• 金额: $ 40万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628224
• 关键词: Acute Myelocytic Leukemia; Agonist; Agranulocytosis; Area; Aspirate substance; Biology; Breathing; Cause of Death; Cell Culture Techniques; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Cultured Cells; Cyclic Neutropenia; Disease; Dose; Employee Strikes; Environment; Epithelial; Epithelial Cells; Epithelium; Event; Face; Gram-Negative Bacteria; Human; Immune; Immunocompromised Host; In Vitro; Infection; Investigation; Knockout Mice; Legal patent; Leukocytes; Lung; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Mucosal Immunity; Mus; Natural Immunity; Neoadjuvant Therapy; Patients; Phosphotransferases; Pneumonia; Population; Predisposition; Prophylactic treatment; Reactive Oxygen Species; Receptor Signaling; Regimen; Reliance; Reporting; Resistance; Respiratory Tract Infections; Risk; Safety; Serum amyloid A protein; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Surface; TNF Receptor-Associated Factors; TRAF6 gene; Technology; Testing; Tissues; Toll-like receptors; Toxic effect; Translations; Viral; aerosolized; airway epithelium; alveolar epithelium; antimicrobial; base; chemotherapy; cytotoxic; fungus; genetic manipulation; immune function; in vitro Model; in vivo; insight; interleukin-1 receptor-associated kinase; killings; leukemia; mouse model; novel; pathogen; patient population; prevent; public health relevance; response; small molecule

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.

项目摘要 肺炎是急性髓样白血病（AML）患者死亡的主要原因。尽管恒定 将巨大组织的巨大表面积暴露于外部环境中，肺的内在 在建立感染之前，防御剂清除了大多数吸气和吸入的病原体。这些相同的粘膜 可以使用新型的吸入疗法来刺激防御措施 像受体（TLR）激动剂组合。这种诱导的抗性与快速肺内有关 病原体杀死并防止小鼠死亡，以免致死的肺炎。 相关的病原体，即使在严重化学疗法诱导的免疫功能障碍的情况下也是如此。这 发现肺上皮细胞是可诱导反应的主要效应子 特别吸引中性粒细胞增生AML患者。该应用建议剖析分子 这种非凡现象的基础机制，以帮助该技术的临床翻译供该技术用于 AML患者并提高人们对新型宿主 - 病原体相互作用的理解。 AIM 1将识别诱导抗AML相关的抗肺上皮细胞种群 肺炎。将通过比较原发性诱导AML病原体来确定贡献 小鼠和人上皮细胞，以及通过小鼠细胞选择性缺陷TLR信号传导的功能测试。 AIM 2将确定白血病细胞会损害诱导性抗性或通过标准治疗 细胞毒性或低甲基化AML方案。这将根据对的影响在体内和体外评估 生存，病原体杀死，上皮活力，细胞活化，抗菌效应子和循环白细胞 AIM 3将剖析诱导抗性的分子机制，以确定保护是否可以 尽管现代靶向分子AML处理共同管理，并促进发现 新型上皮刺激。小鼠基因操纵和体外模型将确定所需的信号传导和 效应子分子，并有望洞悉观察到的无法解释的TLR​​协同作用。 拟议的研究有望鉴定关键细胞，信号通路和效应分子的分子 诱导性抗性，促进发现更有效的抗药性诱导剂，探索意外的TLR 相互作用，评估诱导抗性与AML及其处理的相互作用，识别AML种群 最有可能从治疗中受益，并促进该技术的快速转化为诊所，因此 在峰值脆弱性期间，可以保护AML患者免受致命性肺炎的保护。