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（由适用提供）：脑疟疾是恶性疟原虫感染的致命并发症，与脑微脉管系统中感染性红细胞的大量积累有关。寄生虫结合是由恶性疟原虫红细胞膜蛋白1（PFEMP1）家族介导的。最近，我们发现表达DC8和DC13 PFEMP1的寄生虫与脑疟疾相关，并证明它们通过PFEMP1中的富含半胱氨酸的域中（CIDR）结构域与内皮蛋白C受体（EPCR）结合。 DC8和DC13 PFEMP1结合EPCR的发现对脑疟疾发病机理具有重要意义。 EPCR是活化蛋白C的受体，在调节性凝血和内皮屏障特性中起关键作用。这些发现表明，寄生虫细胞粘附与微血管病理学之间可能存在因果关系，例如通过DC8或表达DC13表达感染的红细胞的蛋白质C-EPCR相互作用的封锁。尽管该机制为大脑疟疾的许多病理生理相关性提供了外观解释，但许多关键问题仍未得到答复，包括DC8和DC13 PFEMP1抑制EPCR功能的程度，并识别介导大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了蛋白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症和促进式功能和3。确定与EPCR一起起作用的宿主受体的组合，以介导DC8 Variants与BrainEnsothials的高亲和力结合。这个项目将 表征了分子机制，通过这种机制，恶性疟原虫感染的红细胞粘附在脑内皮细胞上，阐明了与大脑疟疾相关的致病机制，并可能建议提出抗粘附策略或新的治疗方案，以改善大脑疟疾的癌症。