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: 9194424
• 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/9194424
• 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; Cyclic Neutropenia; Disease; Dose; Employee Strikes; Environment; Epithelial; Epithelial Cells; Epithelium; Event; Face; Gram-Negative Bacteria; Human; Immune; Immune signaling; Immunocompromised Host; Impairment; In Vitro; Infection; Investigation; Knockout Mice; Legal patent; Leukocytes; Lung; Mediating; Mediator of activation protein; Modeling; Modernization; Molecular; Molecular Target; Mucosal Immunity; Mus; Natural Immunity; Neoadjuvant Therapy; Patient risk; Patients; Phosphotransferases; Pneumonia; Population; Predisposition; Prophylactic treatment; Reactive Oxygen Species; Receptor Signaling; Regimen; Reporting; Resistance; Respiratory Tract Infections; Safety; Serum amyloid A protein; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Surface; TNF Receptor-Associated Factors; TRAF6 gene; Technology; Testing; Therapeutic; Tissues; Toll-like receptors; Toxic effect; Translations; Viral; acute toxicity; aerosolized; airway epithelium; alveolar epithelium; antimicrobial; base; chemotherapy; clinical translation; cytotoxic; fungus; genetic manipulation; immune function; in vitro Model; in vivo; insight; interleukin-1 receptor-associated kinase; killings; leukemia; leukemia treatment; mouse model; novel; pathogen; patient population; prevent; public health relevance; response; small molecule; synergism

DESCRIPTION (provided by applicant): 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 whethe 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.

描述（由申请人提供）：肺炎是急性髓系白血病（AML）患者死亡的主要原因。尽管脆弱组织的巨大表面积不断暴露于外部环境，但肺部的内在防御能力在感染发生之前清除了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由非直观的 Toll 样受体 (TLR) 激动剂组合组成的新型吸入疗法进行治疗性刺激。这种诱导性耐药与肺内病原体的快速杀灭有关，即使在严重化疗引起的免疫功能低下的情况下，也能防止小鼠因常见 AML 相关病原体引起的致命性肺炎而死亡。肺上皮细胞是诱导反应的主要效应器这一发现使得这种方法对于中性粒细胞减少性 AML 患者的使用特别有吸引力。本申请旨在剖析这一显着现象背后的分子机制，以帮助该技术在 AML 患者中的临床转化，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 相关肺炎诱导耐药所需的肺上皮细胞群。将通过比较原代小鼠和人上皮细胞对 AML 病原体的诱导杀伤作用以及对 TLR 信号选择性缺陷的小鼠细胞进行功能测试来确定贡献。目标 2 将确定诱导性耐药是否会因白血病细胞或标准细胞毒性或低甲基化 AML 方案的治疗而受损。这将根据对生存、病原体杀灭、上皮活力、细胞活化、抗菌效应物和循环白细胞的影响进行体内和体外评估。目标 3 将剖析诱导耐药的分子机制，以确定在联合给药的情况下保护是否能持续存在现代靶向分子 AML 治疗的进展，并促进新的上皮刺激的发现。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。拟议的研究预计将识别诱导耐药的关键细胞、信号通路和效应分子，促进发现更有效的耐药诱导剂，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，识别最有可能的 AML 群体从治疗中受益，并促进该技术快速转化为临床，从而使 AML 患者在最脆弱时期免受致命性肺炎的侵害。