权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular Mechanisms in Pediatric Cerebral Malaria Pathogenesis and Immunity

小儿脑型疟疾发病机制和免疫的分子机制

基本信息

批准号：
10454338
负责人：
JOSEPH D SMITH
金额：
$ 66.36万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454338
关键词：
3-Dimensional Adhesions Adhesiveness Affinity Antibodies Antibody Response Anticoagulants Autopsy Binding Binding Proteins Biological Markers Biomass Biomechanics Biophysics Blocking Antibodies Blood Blood - brain barrier anatomy Brain Brain Edema Cerebral Malaria Cerebrum Cessation of life Characteristics Child Childhood Clinical Complication Dangerousness Data Devices Dimensions Disease Endothelial Cells Endothelium Erythrocyte Membrane Erythrocytes Feedback Gene Silencing Genes Genetic Transcription Geometry Glycophorin Health Human Immune Immunity Impairment Infection Integration Host Factors Intercellular adhesion molecule 1 Intestines Knowledge Ligands Location Malaria Malawi Mediating Membrane Proteins Microcirculatory Bed Modeling Molecular Obstruction Organ Outcome Parasites Pathogenesis Pathogenicity Pathology Pathway interactions Patients Pediatric cohort Physiological Plasma Plasmodium falciparum Play Property Proteins Risk Role Site Source Structure Supplementation Survivors TNF gene Therapeutic Intervention Transgenic Organisms Tropism Variant Work activated protein C receptor blood damage brain endothelial cell cerebral microvasculature cohort gastrointestinal histidine-rich proteins in vitro Model inhibiting antibody innovation innovative technologies malaria infection malaria transmission mortality new technology novel overexpression pediatric patients placental malaria prevent receptor receptor binding ward

项目摘要

PROJECT ABSTRACT The human malaria parasite Plasmodium falciparum remains one of the most important causes of childhood mortality in the world. Cerebral malaria, the most severe complication of P. falciparum infection, is caused by the sequestration of infected red blood cells in cerebral microvasculature. The var gene or P. falciparum erythrocyte membrane protein 1 (PfEMP1) is the major cytoadhesion ligand for the parasite. While progress has been made in understanding the structure and function of PfEMP1 proteins, the key parasite ligand- receptor interactions involved in cerebral binding remain unestablished. Our recent studies have shown that specific parasite adhesion types are increased in the blood of cerebral malaria patients, and that parasite adhesion to endothelial protein C receptor (EPCR) may impair a key anticoagulant and barrier protective pathway. Moreover, we have shown that hyperlactemia increases fatality risk in pediatric cerebral malaria. However, large knowledge gaps remain in parasite sequestration in brain, in large part due to its inaccessibility and the lack of appropriate in vitro models. We have recently developed an innovative technology using 3D human brain microvessels that recapitulates physiological flow characteristics in health and disease. We are able to fabricate 3D microvessels with different geometries and lumen dimensions, which allow us to study parasite adhesion across a range of flow velocities in a single device, as well as to investigate factors that contribute to microvascular obstruction in malaria. In this project, we will use 3D human brain microvessels in combination with parasite isolates from pediatric cerebral malaria cases to investigate parasite tropism for brain, to identify the precise steps of infected red blood cell capture and firm adhesion on brain endothelial cells, to characterize potential interactions between lactemia and parasite adhesiveness, and to investigate antibody protective mechanisms in cerebral malaria. The proposed studies will advance our understanding of the molecular mechanisms of P. falciparum binding in cerebral malaria and immune mechanisms in anti- disease immunity.

项目摘要