Cell adhesion molecules in cerebral malaria.

脑型疟疾中的细胞粘附分子。

• 批准号: 6690987
• 负责人: HENRI C VAN DER HEYDE
• 金额: $ 31.76万
• 依托单位: LA JOLLA BIOENGINEERING INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690987
• 关键词: B lymphocyte; Plasmodium falciparum; SCID mouse; affinity chromatography; cell adhesion molecules; cell mediated cytotoxicity; cerebrum; cytotoxic T lymphocyte; flow cytometry; fluorescence microscopy; genetically modified animals; helper T lymphocyte; interferon gamma; interleukin 10; interleukin 2; laboratory mouse; lung; malaria; parasite infection mechanism; pathologic process; polymerase chain reaction; respiratory insufficiency /failure; shock; suppressor T lymphocyte; western blottings

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.

描述（由申请人提供）：尽管经过数十年的努力来征服 疟疾仍然是单一传染源导致死亡的主要原因。 恶性疟原虫和杀虫剂产生耐药性的出现 蚊媒的抵抗力共同推动了针对蚊子的治疗的发展 疟疾非常可取。虽然预防感染的疫苗是值得称赞的 目标，开发治疗方法来控制病理后果 疟疾可能是一个更可行的解决方案。为了开发这样的疗法，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 姿势导致意识受损（脑疟疾）、呼吸系统疾病 乳酸性酸中毒、贫血和（罕见）急性肾炎的困扰。发展 根据世界卫生组织的说法，休克是预后不良的一个指标。在 此外，恶性疟原虫患者的内皮细胞活化程度增加 许多细胞粘附分子（CAM）在内皮上的表达。 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中。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，还会导致循环性休克和呼吸窘迫 乳酸性酸中毒。因此，该模型对于机械地剖析非常有用 CAM 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性标记技术来评估 CAM 内皮细胞表达和流式细胞术评估 T 上的 CAM 表达 伯氏疟原虫疟疾期间的细胞。 P 期间 CAM 表达增加。 将测试伯盖疟疾在脑型疟疾中的作用 使用 CAM0/0 和抗 CAM mAb 治疗的小鼠进行呼吸窘迫。 通常需要促炎细胞因子来增加 CAM 表达，因此我们 将确定选定的促炎细胞因子是否在 疟疾的发病机制是通过调节 CAM 表达来实现的。我们的初步数据 表明 CAM 和促炎细胞因子确实是 伯氏疟疾的发病机制。我们将测试是否抑制 细胞内信号通路（特别是 NF-κB）消除脑型疟疾 通过防止 CAM 表达和 T 细胞增加来缓解呼吸窘迫 与内皮细胞的粘附。