Adhesive Interactions in Severe Malaria

严重疟疾中的粘合剂相互作用

• 批准号: 9087147
• 负责人: JOSEPH D SMITH
• 金额: $ 59.48万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-24 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087147
• 关键词: Adhesions; Adhesives; Affect; Affinity; Apoptosis; Autopsy; Binding; Biological; Blood Coagulation Disorders; Brain; Cell membrane; Cerebral Malaria; Cerebrum; Childhood; Coagulation Process; Complication; Cysteine; Disease; Endothelial Cells; Erythrocyte Membrane; Erythrocytes; Family; Health; Human; Infection; Inflammation; Intervention; Lead; Ligands; Light; Link; Malaria; Maps; Mediating; Membrane Proteins; Modeling; Molecular; Outcome; Parasites; Pathogenesis; Patient-Focused Outcomes; Patients; Permeability; Plasmodium falciparum; Play; Property; Protein Array; Protein C; Proteins; Research; Serum; Thrombin; Variant; Vascular Permeabilities; activated protein C receptor; base; brain endothelial cell; cerebral microvasculature; design; improved; insight; microvascular pathology; receptor; research study

 DESCRIPTION (provided by applicant): Cerebral malaria is a deadly complication of Plasmodium falciparum infection that is associated with the massive accumulation of infected erythrocytes in cerebral microvasculature. Parasite binding is mediated by the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. Recently, we discovered that parasites expressing DC8 and DC13 PfEMP1 are associated with cerebral malaria and showed that they bind to endothelial protein C receptor (EPCR) via the cysteine-rich interdomain region (CIDR) domain in PfEMP1. The finding that DC8 and DC13 PfEMP1 bind EPCR has important implications for cerebral malaria pathogenesis. EPCR is a receptor for activated protein C and plays a key role in regulating coagulation and endothelial barrier properties. These findings suggest there may be causal links between parasite cytoadhesion and microvascular pathology, such as a blockade of the protein C-EPCR interaction by DC8 or DC13-expressing infected erythrocytes. While this mechanism provides an appealing explanation for many of the pathophysiological correlates of cerebral malaria, a number of critical questions remain unanswered including to what extent DC8 and DC13 PfEMP1 inhibit EPCR function and identifying the combination of host receptors mediating cerebral binding. In this project, we will: 1. Determine if EPCR-binding parasites inhibit the protein C-EPCR interaction, 2. Determine if EPCR-binding parasites affect the cytoprotective and pro-barrier function of EPCR on endothelial cells and 3. Determine the combination of host receptors that act in concert with EPCR to mediate high affinity binding of DC8 variants to brain endothelial cells. This project will characterize the molecular mechanisms by which P. falciparum-infected erythrocytes adhere to brain endothelial cells, shed light on the pathogenic mechanisms associated with cerebral malaria, and may suggest anti-adhesive strategies or new treatment options to improve cerebral malaria outcomes.

 描述（由申请人提供）：脑型疟疾是恶性疟原虫感染的致命并发症，与脑微血管系统中受感染红细胞的大量积聚有关。寄生虫结合由恶性疟原虫红细胞膜蛋白1（PfEMP 1）家族介导。最近，我们发现表达DC 8和DC 13 PfEMP 1的寄生虫与脑型疟疾相关，并表明它们通过PfEMP 1中的富含半胱氨酸的域间区域（CIDR）结构域与内皮蛋白C受体（EPCR）结合。DC 8和DC 13 PfEMP 1结合EPCR的发现对脑型疟疾发病机制具有重要意义。EPCR是活化蛋白C的受体，在调节凝血和内皮屏障特性中起关键作用。这些发现表明寄生虫细胞粘附和微血管病理学之间可能存在因果关系，例如DC 8或DC 13表达感染红细胞对蛋白质C-EPCR相互作用的阻断。虽然这种机制为脑型疟疾的许多病理生理学相关性提供了一个有吸引力的解释，但许多关键问题仍未得到解答，包括DC 8和DC 13 PfEMP 1在多大程度上抑制EPCR功能以及鉴定介导脑结合的宿主受体的组合。在这个项目中，我们将： 1.确定EPCR结合寄生虫是否抑制蛋白质C-EPCR相互作用，2.确定EPCR结合寄生虫是否影响EPCR对内皮细胞的细胞保护和促屏障功能;确定与EPCR协同作用以介导DC 8变体与脑内皮细胞的高亲和力结合的宿主受体的组合。该项目将 描述了恶性疟原虫感染的红细胞粘附于脑内皮细胞的分子机制，阐明了与脑型疟疾相关的致病机制，并可能提出抗粘附策略或新的治疗方案，以改善脑型疟疾的结局。