Macrophage drug transport and metabolism in the outcome of antileishmania therapy

描述(由申请人提供)：目前没有预防利什曼病的疫苗，病媒管理战略目前不可持续。因此，抗利什曼药物化疗是唯一可用的控制措施。尽管如此，拉丁美洲一线药物的治疗失败率很高(在5%到5%之间) 75%)。虽然失败通常被解释为寄生虫耐药性的结果，但治疗反应是多因素的，证据支持宿主因素在 治疗结果。然而，潜在的药理学、免疫学和代谢事件，相关的调节机制，以及它们在个体之间的差异尚不清楚。为了优化可用于治疗由利什曼原虫引起的皮肤利什曼病的化疗的有效性，该项目试图确定与治疗结果成功或失败相关的宿主生物标志物。我们将使用全面的实验设计，整合有针对性的、假设驱动的方法学方法，包括治疗失败的药物基因组签名，以及最先进的无偏见的生物标记物发现方法和与宿主细胞药物反应有关的功能验证宿主基因(代谢图谱和shRNA文库筛选)。该项目的具体目的是确定治疗结果的药理学相关性。该项目的结果将产生对在抗利什曼药物化疗和个体内发生的变异的背景下宿主-病原体相互作用的关键理解，将有助于了解宿主细胞对抗利什曼药物的药物反应的机制，并将允许识别治疗反应的生物标记物。这项研究将挑战目前治疗利什曼病的方法，提供临床前的信息，说明多标记生物签名作为预测和/或预测治疗结果的工具的有用性。它还将推动针对细胞内药物生物利用度的创新联合疗法的开发。整合这些发现将为改进疾病管理和控制提供基础，这是基于对治疗反应的早期预测和优化的治疗干预措施。

DESCRIPTION (provided by applicant): There are no vaccines available to prevent leishmaniasis and vector management strategies are currently unsustainable. As a consequence, antileishmanial chemotherapy is the only control measure available. Despite this fact, there are high rates of treatment failure to first line drugs in Latin America (between 5 and 75%). Although failure is frequently interpreted as a consequence of parasite drug resistance, the therapeutic response is multifactorial, and evidence supports a central role of host factors in treatment outcome. However, the underlying pharmacological, immunological and metabolic events, the associated regulatory mechanisms, and their variation among individuals are unknown. To optimize the usefulness of available chemotherapy for cutaneous leishmaniasis caused by Leishmania Viannia, this project seeks to identify host biomarkers associated with successful or failed treatment outcomes. We will use a comprehensive experimental design integrating targeted, hypothesis-driven methodological approaches including pharmacogenomic signatures of treatment failure, and state-of-the-art unbiased methodologies for biomarker discovery and functional validation host genes involved in host cell drug-responsiveness (metabolic profiling and shRNA library screening). This project specifically aims to identify pharmacological correlates of the therapeutic outcome. Results from this project will generate critical understanding of host-pathogen interactions in the context of antileishmanial chemotherapy and variations that occur within individuals, will inform on the mechanisms of drug responsiveness of host cells to antileishmanial drugs, and will allow the identification of biomarkers of treatment response. This investigation will challenge current approaches for the treatment of leishmaniasis by providing pre-clinical information of the usefulness of multi-marker biosignatures as predictive and/or prognostic tools of therapeutic outcome. It will also drive the development of innovative combination therapies that target intracellular drug bioavailability. Integration of these findings will provide the bases for improved disease management and control, based on early predictions of treatment response and optimized therapeutic interventions.