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）：尽管几十年的努力征服