3D human-based microvessel bed for the study of Plasmodium falciparum interacting with vessel wall

用于研究恶性疟原虫与血管壁相互作用的 3D 人体微血管床

• 批准号: 9015016
• 负责人: JOSEPH D SMITH
• 金额: $ 57.28万
• 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: 2015-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015016
• 关键词: Adhesions; Animal Model; Antibodies; Apoptosis; Beds; Binding; Blood - brain barrier anatomy; Blood Circulation; Blood Platelets; Blood Vessels; Blood coagulation; Brain; Cells; Cerebral Malaria; Cerebrum; Coagulants; Coagulation Process; Coculture Techniques; Collagen; Complex; Complication; Dermal; Dermis; Disease; Endothelial Cells; Engineering; Erythrocyte Membrane; Erythrocytes; Family; Fibrin; Functional disorder; Heart; Hour; Human; In Vitro; Inflammation; Integration Host Factors; Intervention; Lead; Life; Light; Lung; Malaria; Mediating; Membrane Proteins; Microarray Analysis; Microcirculatory Bed; Modeling; Molecular; Monitor; Organ; Parasites; Pathogenesis; Pathway interactions; Physiological; Pigments; Plasmodium falciparum; Play; Property; Protein C; Proteins; Recombinant Proteins; Role; Series; Serum; Signal Pathway; Site; Spleen; System; Technology; Thrombosis; Thrombus; Tight Junctions; Time; Tropism; Variant; Vascular Diseases; Vascular Permeabilities; Virulence; abstracting; activated protein C receptor; angiogenesis; base; cytokine; endothelial dysfunction; improved; killings; monocyte; novel; novel strategies; public health relevance; research study; sample fixation; scaffold; success; therapeutic development

 DESCRIPTION (provided by applicant): Cytoadhesion of Plasmodium falciparum infected erythrocytes is a major virulence determinant that enables parasites to sequester from blood circulation by binding to the endothelial lining of blood vessels and avoid spleen-dependent killing mechanisms. Whereas infected erythrocytes sequester in a variety of microvascular beds, cerebral malaria is a life-threatening disease complication that is associated with massive sequestration in brain microvessels. Cerebral malaria is accompanied by endothelial activation, blood-brain barrier disruption and fibrin thrombi at sites of infected erythrocyte sequestration. While progress has been made in understanding the binding properties of infected erythrocytes, critical questions remain unanswered about the mechanisms of cerebral malaria pathogenesis. Binding of P. falciparum- infected erythrocytes is mediated by the large and diverse P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. We recently showed that severe malaria is associated with a distinct subset of PfEMP1 variants that binds to endothelial protein C receptor, an important regulator of blood clotting and endothelial activation. Our preliminary findings suggest that parasites may impair EPCR function and lead to cerebral malaria complications. However, a significant barrier to investigating disease mechanisms in human cerebral malaria is the inaccessibility of the brain. This project will exploit new advances in microvascular engineering technology in the study of human cerebral malaria. By building a human brain microvascular model, we will: 1. Characterize the molecular mechanisms by which P. falciparum-infected erythrocytes adhere to human brain endothelial cells and other microvascular beds using in vitro 3D human microvascular systems. 2. Determine the consequent changes on the barrier and thrombogenic properties of the vessel wall. 3. Determine host signaling pathways engaged by the infected erythrocyte-endothelial activation that are associated with endothelial dysfunction or protection. The success of the project will shed light on the pathogenic mechanisms associated with cerebral malaria and may guide potential therapeutic development.

 描述（由申请人提供）：恶性疟原虫感染的红细胞的细胞粘附是主要的毒力决定因素，它使寄生虫能够通过与血管内皮衬里结合而隔离在血液循环中，并避免依赖脾脏的杀伤机制。受感染的红细胞隔离在各种微血管床中，而脑型疟疾是一种危及生命的疾病并发症，与脑微血管中的大量隔离有关。脑型疟疾伴随着内皮细胞激活、血脑屏障破坏以及受感染红细胞隔离部位的纤维蛋白血栓。尽管在了解受感染红细胞的结合特性方面取得了进展，但有关脑型疟疾发病机制的关键问题仍未得到解答。恶性疟原虫感染的红细胞的结合是由大型且多样化的恶性疟原虫红细胞膜蛋白 1 (PfEMP1) 家族介导的。我们最近表明，严重的疟疾与 PfEMP1 变体的一个独特子集有关，该变体与内皮蛋白 C 受体结合，内皮蛋白 C 受体是血液凝固和内皮激活的重要调节因子。我们的初步研究结果表明，寄生虫可能会损害 EPCR 功能并导致脑型疟疾并发症。然而，研究人类脑型疟疾疾病机制的一个重大障碍是大脑的不可接近性。该项目将利用微血管工程技术的新进展来研究人类脑型疟疾。通过构建人脑微血管模型，我们将： 1. 使用体外 3D 人体微血管系统表征恶性疟原虫感染的红细胞粘附到人脑内皮细胞和其他微血管床的分子机制。 2. 确定血管壁屏障和血栓形成特性的后续变化。 3. 确定与内皮功能障碍或保护相关的受感染红细胞内皮激活所涉及的宿主信号传导途径。该项目的成功将揭示与脑型疟疾相关的致病机制，并可能指导潜在的治疗开发。