Cell adhesion molecules in cerebral malaria.

脑型疟疾中的细胞粘附分子。

基本信息

批准号：
6935256
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
项目类别：
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

项目摘要

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。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nitric oxide is neither necessary nor sufficient for resolution of Plasmodium chabaudi malaria in mice.

一氧化氮对于解决小鼠中的恰鲍迪疟原虫疟疾既不是必要的也不是充分的。

DOI：
10.4049/jimmunol.165.6.3317
发表时间：
2000
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
vanderHeyde,HC;Gu,Y;Zhang,Q;Sun,G;Grisham,MB
通讯作者：
Grisham,MB

Platelet depletion by anti-CD41 (alphaIIb) mAb injection early but not late in the course of disease protects against Plasmodium berghei pathogenesis by altering the levels of pathogenic cytokines.

DOI：
10.1182/blood-2004-06-2206
发表时间：
2005-03
期刊：
Blood
影响因子：
20.3
作者：
H. C. van der Heyde;I. Gramaglia;Guang Sun;C. Woods
通讯作者：
H. C. van der Heyde;I. Gramaglia;Guang Sun;C. Woods

Plasmodium chabaudi adami: use of the B-cell-deficient mouse to define possible mechanisms modulating parasitemia of chronic malaria.

Plasmodium chabaudi adami：使用 B 细胞缺陷小鼠来确定调节慢性疟疾寄生虫血症的可能机制。

DOI：
10.1016/j.exppara.2005.06.006
发表时间：
2005
期刊：
Experimental parasitology.
影响因子：
0
作者：
Weidanz,WilliamP;Batchelder,JoanM;Flaherty,P;LaFleur,G;Wong,C;vanderHeyde,HC
通讯作者：
vanderHeyde,HC

Impairment of functional capillary density but not oxygen delivery in the hamster window chamber during severe experimental malaria.

在严重的实验性疟疾期间，功能性毛细血管密度受损，但仓鼠窗室中的氧气输送并未受损。