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）：肺炎是急性髓样白血病（AML）患者死亡的主要原因。尽管在外部环境中持续不断暴露于巨大的组织，但在建立感染之前，肺的内在防御能力清楚地清楚了最受吸入和吸入的病原体。这些相同的粘膜防御剂可以通过通过非直觉Toll-Like受体（TLR）激动剂组合组成的新型吸入疗法进行治疗刺激。这种诱导性耐药性与快速肺内病原体杀死有关，并防止小鼠死亡，否则是由普通AML相关的病原体引起的致命性肺炎，即使在严重化学疗法诱导的免疫局势也是如此。发现肺上皮细胞是可诱导反应的主要效应因素的发现，这种方法特别吸引了中性粒细胞AML患者的使用。该应用建议剖析这种非凡现象的基础机制，以帮助该技术用于AML患者的临床翻译，并促进对新型宿主 - 病原体相互作用的理解。 AIM 1将识别诱导抗AML相关性肺炎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病原体的诱导杀伤以及小鼠细胞选择性缺陷TLR信号传导的功能测试来确定贡献。 AIM 2将确定白血病细胞或用标准的细胞毒性或低甲基化AML方案治疗诱导性抗性。这将根据对生存，病原体杀死，上皮活性，细胞活化，抗菌效应子以及循环白细胞的目标的影响的影响进行体内和体外评估。小鼠遗传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诱导性耐药性的关键细胞，信号通路和效应分子，促进发现更有效的耐药性诱导者，探索意外的TLR相互作用，评估诱导性TLR相互作用，评估诱导性抗性与AML及其处理及其处理及其处理的相互作用，并鉴定出最可能从该技术中受益的AML群体，从而使该技术受益于该技术，并且可以使该技术受益于该技术，因此，该技术的临床能力是如此，这是该技术的临床，因此，该技术的临床能力是如此，这是该技术的转化，并且可以使该技术受益于该技术，并且可以使该技术受益匪浅。高峰脆弱性期间的肺炎。