Cell adhesion molecules in cerebral malaria.

描述（由申请人提供）：尽管几十年的努力征服 疟疾仍然是单一传染源导致死亡的主要原因。 恶性疟原虫抗药性的产生与杀虫剂 蚊子媒介的抗药性共同使得针对 疟疾非常可取。虽然预防感染的疫苗是值得称赞的， 目标，治疗的发展，以控制的病理后果， 疟疾可能是一个更容易实现的解决办法。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 恶性疟原虫患者的临床研究表明，这些人 出现意识障碍和姿势（脑型疟疾），呼吸道 乳酸酸中毒、贫血和（罕见）急性肾炎。发展 根据世界卫生组织的说法，休克是预后不良的预后指标。在 此外，恶性疟原虫患者的内皮细胞活化， 在内皮上表达许多细胞粘附分子（CAM）。 总的来说，这些发现表明循环休克的过程 发生在恶性疟原虫疟疾患者身上。我们最近的工作 实验室表明，感染伯氏疟原虫的小鼠，一种公认的模型， 脑型疟疾，也会出现循环休克和呼吸窘迫， 乳酸性酸中毒因此，该模型对于机械地剖析 CAMs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重放射性标记技术来评估CAM 用流式细胞术检测T细胞上CAM的表达， 伯氏疟原虫疟疾期间的细胞。在P. 将测试伯氏疟疾在脑型疟疾中的作用， 通过使用CAM 0/0和抗CAM mAb处理的小鼠观察呼吸窘迫。 通常需要促炎细胞因子来增加CAM表达，所以我们 将决定选择的促炎细胞因子是否在 疟疾的发病机制通过调节CAM的表达。我们的初步数据 表明CAM和促炎细胞因子确实是 伯氏疟原虫疟疾的发病机制。我们将测试是否抑制一个 细胞内信号通路（特别是NF-？B）消除脑型疟疾 通过防止CAM表达增加和T细胞 粘附于内皮。

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.