NIH - NHLBI - Re-Entry Supplement to Existing R01 Variant surface antigens in cerebral malaria pathogenesis

NIH - NHLBI - 脑型疟疾发病机制中现有 R01 变异表面抗原的重新进入补充

• 批准号: 9443388
• 负责人: Steven A. Fisher
• 金额: $ 14.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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/9443388
• 关键词: Acute; Africa South of the Sahara; Anemia; Animal Model; Antibodies; Antibody Formation; Antibody-mediated protection; Anticoagulation; Antigens; Autopsy; Binding; Binding Proteins; Blood Vessels; Blood capillaries; Brain; CD36 gene; Cardiovascular system; Case-Control Studies; Cerebral Malaria; Cerebrovascular Disorders; Child; Clinical; Collaborations; Communities; Congestive; Convalescence; Custom; Cytoprotection; Data; Development; Erythrocyte Membrane; Erythrocytes; Etiology; Family; Functional disorder; Gene Family; Genes; Genetic; Genome; Genomics; Goals; Human; Hypoxia; Immune; Immune system; Immunity; Impairment; Individual; Infection; Inflammation; Kidney Failure; Lead; Life; Link; Malaria; Malaria Vaccines; Mali; Measures; Membrane; Membrane Proteins; Mus; National Heart, Lung, and Blood Institute; Natural Immunity; Open Reading Frames; Organ; Parasites; Pathogenesis; Pathway interactions; Patients; Plasmodium falciparum; Play; Protein C; Protein Family; Protein Fragment; Protein Microchips; Proteins; Proteomics; Reporter; Research; Research Technics; Respiratory distress; Role; Rural; Sampling; Severities; Site; Spleen; Subgroup; Surface; Surface Antigens; Syndrome; System; United States National Institutes of Health; Vaccines; Variant; Vascular Diseases; Virulence; Work; activated protein C receptor; brain tissue; capillary; case control; cerebral oxygenation; humanized mouse; killings; malaria infection; mouse model; next generation sequencing; novel; parasite genome; prevent; public health relevance; receptor; whole genome

 DESCRIPTION (provided by applicant): Cerebral malaria is the deadliest form of malaria, potentially killing half of its victims-primarily children in sub- Saharan Africa. However, most children in malaria-endemic regions appear to develop immunity to severe malaria early in life, a phenomenon that correlates with the production of antibodies to malaria parasite antigens that are expressed on the surface of infected erythrocytes. These variant surface antigens (VSAs) are the most polymorphic families within the parasite genome: Plasmodium falciparum erythrocyte membrane proteins (PfEMP1), repetitive interspersed family proteins (RIFINs) and the sub-telomeric variable open reading frame proteins (STEVORs). Each malaria genome has hundreds of genes encoding these diverse parasite surface antigens, of which only a small subset are expressed on the surface of a given infected erythrocyte. If a subset of VSAs is specific to cerebral malaria, they would be an important target for a malaria vaccine to protect children and travelers from the deadliest consequences of malaria. Work at our field site in rural Mali suggests that malaria parasites express a "stealth" subgroup of these parasite surface antigens more commonly in cerebral malaria than in milder forms of malaria. Our overall goals are to determine the VSA contribution to the pathophysiology of cerebral malaria and the importance of an individual's development of antibodies to VSAs in the acquisition of immunity to cerebral malaria. This project combines novel genomic and proteomic approaches with the use of a new animal model to measure the association between particular variant surface antigens and the development of cerebral malaria and also protective natural immunity. We will determine the genetic sequences of VSAs in cerebral malaria infections and in matched uncomplicated malaria controls in a cerebral malaria case-control study and ascertain which VSAs are found on the surface on infected erythrocytes (Aim 1). Mice will be infected with these field-derived parasites and the microvascular pathophysiological effects will be identified in the brain, including associations with expressed VSAs (Aim 2). Multiple VSA fragments will be encoded onto microarray chips, which will then be exposed to patients' sera to study antibody interactions with all of these proteins at once (Aim 3). This project introduces cutting-edge research techniques-some from outside the malaria research community-including next-generation sequencing, custom microarrays, proteomics, and a promising new animal model, to advance our understanding of cerebral malaria and the development of a cerebral malaria vaccine.

 描述（由申请人提供）：脑疟疾是撒哈拉以南非洲疟疾的日期形式，但是，大多数疟疾 - 疟疾地区的儿童似乎在生命早期就对Severia产生了免疫力寄生虫。 。寄生虫表达寄生虫表面抗原的“隐形”亚组，而不是在疟疾的温和形式中对脑病的病理生理学的贡献。该项目将新型的基因组和蛋白质组学方法与特定变异抗原和脑发育之间的离子使用，并在脑疟疾中的VSA的网络序列在匹配的疟疾控制中。 l效果将在大脑中鉴定出与明确的VSA的含有相关性（AIM 2） ，蛋白质组学和一种有希望的新动物模型，可以提高我们对小脑的理解和脑疟疾疫苗的发展。