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

马拉维疟疾疾病的决定因素，5U19AIO89683-02，“竞争性修订

• 批准号: 8412261
• 负责人: Terrie Ellen Taylor
• 金额: $ 23.19万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8412261
• 关键词: Determinants; Malaria; Disease; Malawi; 5U19AIO89683

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.

描述（由申请人提供）：严重的疟疾（SM）给撒哈拉以南非洲儿童带来了不成比例的死亡和死亡负担。由于SM的导致死亡不是寄生虫负荷的直接结果，而是与SM患者的大脑和肺中过度炎症反应有关。先天免疫反应的寄生虫衍生的激活剂以及炎症单核细胞与介导这种组织损伤有关。但是，负责局部炎症和损害血脑屏障（BBB）的激活途径仍有待确定。我们提出了阐明机制的：1。定义小儿SM组织中损伤部位的转录曲线。我们建议在大脑中组织损伤部位和小儿SM患者的肺部损害部位组装一个转录“路线图”。表达模式将通过对SM患者的更广泛的存档组织的免疫 - 历史分析来验证。 2。载有血元的外周血单核细胞是否证明了介导或加剧组织损伤的能力？我们将对来自SM患者的血量化，外周血单核细胞进行转录和功能键入，以确定其炎症活动是否与在特定目标1中阐明的组织损害途径相关。 3。这些潜在破坏性细胞是否可以通过适当的抗炎药或免疫调节剂重新编程？我们提出了针对患者载体的单核细胞的一组抗炎化合物的体外筛选，以鉴定能够破坏导致SMS组织损伤和死亡的激活级联反应的化合物。 该项目的目标旨在在SM患者队列中对疾病的病理产生机械理解，这是父母ICEMR赠款的主题。