Cell adhesion molecules in cerebral malaria.

描述(由申请者提供)：尽管几十年的努力征服 尽管疟疾是一种单一的传染病，但它仍然是导致死亡的主要原因。 恶性疟原虫的抗药性与杀虫剂 蚊媒的抗药性共同推动了治疗方法的发展 疟疾是非常可取的。虽然预防感染的疫苗是值得称赞的 目标，发展治疗以控制疾病的病理后果 疟疾可能是一种更可实现的解决方案。为了开发这种疗法，我们 需要详细了解疟疾的病理生理学。结果来自 对恶性疟原虫患者的临床研究表明，这些人 因姿势(脑性疟疾)、呼吸系统疾病而出现意识障碍 伴有乳酸中毒、贫血和(极少数)急性肾炎的痛苦。发展 根据世界卫生组织的说法，休克是一个预后不良的指标。在……里面 此外，恶性疟原虫患者激活的内皮细胞数量增加。 内皮细胞表达多种细胞黏附分子(CAM)。 总的来说，这些发现表明，循环系统休克的过程 都发生在恶性疟患者身上。来自我们的最新工作 实验室表明，感染伯氏疟原虫的小鼠是一种公认的 脑型疟疾，也会出现循环系统休克和呼吸窘迫 乳酸中毒。因此，这个模型对于机械地剖析 细胞间黏附分子在脑型疟疾和呼吸窘迫发展中的作用。 我们将使用最近开发的双放射标记技术来评估CAM 内皮细胞表达和流式细胞术检测T细胞表面细胞黏附分子表达 伯氏疟原虫期间的细胞。CaM在P. Berghei疟疾将接受测试，以确定它们在脑型疟疾和 用CAM0/0和抗CAM0/0单抗处理的小鼠呼吸窘迫。 促炎症细胞因子通常需要增加CAM的表达，所以我们 将确定选定的促炎细胞因子是否在 调节细胞黏附分子表达在疟疾发病机制中的作用我们的初步数据 表明细胞间黏附分子和促炎细胞因子确实是 伯氏疟原虫的致病机制。我们将测试是否抑制一种 细胞内信号通路(特别是核因子-？B)消除脑型疟疾 通过阻止CAM表达和T细胞的增加而导致呼吸窘迫 黏附于内皮细胞。

DESCRIPTION (provided by the applicant): Despite decades of effort to conquer malaria, it remains a leading cause of death due to a single infectious agent. The advent of drug-resistance by Plasmodium falciparum and insecticide resistance by the mosquito vector jointly makes development of therapy against malaria highly desirable. While a vaccine to prevent infection is a laudable goal, the development of therapy to control the pathological consequences of malaria may represent a more achievable solution. To develop such a therapy, we need a detailed understanding of the pathophysiology of malaria. Results from clinical studies of P. falciparum patients indicate that these individuals develop impaired consciousness with posturing (cerebral malaria), respiratory distress with lactic acidosis, anemia and (rarely) acute nephritis. Development of shock is, according to the WHO, a prognostic indicator of poor outcome. In addition, patients with P. falciparum have activated endothelium with increased expression on endothelium of a number of cell adhesion molecules (CAMs). Collectively these findings indicate that the processes of circulatory shock are occurring in patients with P. falciparum malaria. Recent work from our laboratory indicates that P. berghei-infected mice, a well-recognized model of cerebral malaria, also develop circulatory shock and respiratory distress with lactic acidosis. This model is therefore useful to mechanistically dissect the role of CAMs in the development of cerebral malaria and respiratory distress. We will use the recently developed dual radiolabel technique to assess CAM expression on endothelium and flow cytometry to assess CAM expression on T cells during P. berghei malaria. CAMs with increased expression during P. berghei malaria will be tested for their role in cerebral malaria and respiratory distress by using CAM0/0 and anti-CAM mAb-treated mice. Pro-inflammatory cytokines are often needed to increase CAM expression, so we will determine whether selected pro-inflammatory cytokines function in pathogenesis of malaria by regulating CAM expression. Our preliminary data indicate that both CAMs and pro-inflammatory cytokines are indeed required for pathogenesis of P. berghei malaria. We will test whether inhibition of an intracellular signaling pathway (specifically NF-?B) abrogates cerebral malaria and respiratory distress by preventing increased CAM expression and T cell adherence to endothelium.