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.

项目概要 肺炎是急性髓系白血病（AML）患者死亡的主要原因。尽管不断 脆弱组织的巨大表面积暴露于外部环境，肺部的内在 在感染发生之前，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 可以使用一种新型吸入疗法来刺激防御，该疗法由非直观的 Toll- 样受体（TLR）激动剂组合。这种诱导性阻力与肺内快速 杀死病原体并防止小鼠因常见 AML 引起的致命性肺炎而死亡 相关病原体，即使是在严重化疗引起的免疫功能低下的情况下。这 肺上皮细胞是诱导反应的主要效应器的发现使得这种方法成为可能 尤其适用于中性粒细胞减少的 AML 患者。该应用程序旨在剖析分子 这一非凡现象背后的机制有助于该技术的临床转化以用于 AML 患者并促进对新型宿主-病原体相互作用的理解。 目标 1 将确定对 AML 相关的诱导耐药所需的肺上皮细胞群 肺炎。将通过比较原发性白血病病原体的诱导杀灭作用来确定贡献 小鼠和人类上皮细胞，并通过对 TLR 信号选择性缺陷的小鼠细胞进行功能测试。 目标 2 将确定白血病细胞或标准治疗是否会损害诱导耐药性 细胞毒性或低甲基化 AML 方案。这将根据对体内和体外的影响进行评估 生存、病原体杀灭、上皮活力、细胞激活、抗菌效应和循环白细胞 目标 3 将剖析诱导抗性的分子机制，以确定保护是否可以 尽管同时使用现代靶向分子 AML 治疗，但仍持续存在，并促进发现 新的上皮刺激。小鼠基因操作和体外模型将识别所需的信号传导和 效应分子，并有望深入了解观察到的无法解释的 TLR 协同作用。 拟议的研究预计将鉴定关键细胞、信号通路和效应分子 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，评估诱导耐药性与 AML 及其治疗的相互作用，识别 AML 人群 最有可能从治疗中受益，并促进这项技术快速转化为临床，因此 AML 患者在最脆弱时期可以免受致命性肺炎的影响。