Determinants of Malaria Disease in Malawi, 5U19AIO89683-02, "Competitive Revision

描述（由申请人提供）：严重疟疾（SM）给撒哈拉以南非洲的儿童带来了不成比例的死亡负担。SM导致的死亡不是寄生虫负荷的直接后果，而是与SM患者脑和肺中的过度炎症反应相关。寄生虫衍生的先天性免疫应答激活剂与炎性单核细胞一起参与介导这种组织损伤。然而，负责局部炎症和损害血脑屏障（BBB）的激活途径仍有待确定。我们建议通过以下方式阐明机制：1.定义儿科SM组织损伤部位的转录谱。我们建议组装一个转录的“路线图”的表达谱在组织损伤的部位在大脑和肺部的儿童SM患者。将通过对来自SM患者的更广泛存档组织库的免疫组织学分析来验证表达模式。2.负载疟原虫色素的外周血单核细胞是否具有介导或加重组织损伤的能力？我们将对SM患者的装载有疟原虫色素的外周血单核细胞进行转录和功能分型，以确定其炎症活性是否与特定目标#1中阐明的组织损伤途径相关。3.这些潜在的破坏性细胞能否被适当的抗炎药物或免疫调节剂重新编程？我们建议在体外筛选一组抗炎化合物对患者的疟原虫色素负载的单核细胞，以确定化合物能够化解激活级联反应，导致组织损伤和死亡的SM。 这个项目的目标是产生一个机械的理解疾病的病理学在SM患者队列，这是父母ICEMR补助金的主题。

DESCRIPTION (provided by applicant): Severe malaria (SM) places a disproportionate burden of mortality and death on the children of Sub-Saharan Africa. Death, as a result of SM, is not a direct consequence of parasite load but is associated with excessive inflammatory response(s) in the brain and lungs of SM patients. Parasite-derived activators of the innate immune response, together with inflammatory monocytes, have been implicated in mediating this tissue damage. However, the activation pathways responsible for localized inflammation and compromising the blood brain barrier (BBB) remain to be determined. We propose elucidating the mechanism(s) by: 1. Defining the transcriptional profiles at the sites of damage in tissues from pediatric SM. We propose assembling a transcriptional "road map" of the expression profiles at the sites of tissue damage in the brain and lungs of pediatric SM patients. The expression patterns will be validated by immuno-histological analysis of a broader bank of archived tissues from SM patients. 2. Do hemozoin-loaded peripheral blood monocytes demonstrate the capacity to mediate or exacerbate tissue damage? We will perform transcriptional and functional typing of hemozoin-loaded, peripheral blood monocytes from SM patients to determine whether or not their inflammatory activities correlate with the tissue-damaging pathways elucidated in Specific Aim #1. 3. Can these potentially damaging cells be re-programed by appropriate anti-inflammatory drugs or immune-modulators? We propose in vitro screening of a panel of anti-inflammatory compounds against patients' hemozoin-loaded monocytes to identify compounds capable of defusing the activation cascades that lead to tissue damage and death in SM. The goals of this project are designed to generate a mechanistic understanding of the pathology of disease in the SM patient cohort that is the subject of the parent ICEMR grant.