Pathogenesis of Life Threatening Box Jellyfish Envenomation and Irukandji Syndrome

危及生命的箱形水母中毒和伊鲁坎吉综合征的发病机制

• 批准号: 9169580
• 负责人: ANGEL ANNE YANAGIHARA
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169580
• 关键词: Abdominal Pain; Accounting; Acute; Address; Animal Model; Anxiety; Arachidonic Acids; Area; Australia; B-Lymphocytes; Biochemical; Biochemical Markers; Biogenic Amines; Biological; Biological Assay; Biological Models; Blood; Blood Cells; Blood Platelets; Blood Pressure; Blood Volume; Bradycardia; Cardiac Output; Caribbean region; Catecholamines; Cell surface; Cells; Cerebral hemisphere hemorrhage; Cessation of life; Chest Pain; Clinical; Complementary DNA; Complex; Cubozoa; Development; Diagnostic; Dose; Electrocardiogram; Endothelial Cells; Erythrocytes; Event; Family; Fatal Outcome; Florida; Functional disorder; Genetic Transcription; Goals; Guam; Hawaii; Headache; Heart Rate; Hemolysis; Hour; Human; Hypertension; Hypotension; Immune; In Vitro; Increased sweating; Indian Ocean; Indonesia; Inflammatory; Injection of therapeutic agent; Jellyfish; Kidney; Leukocytes; Life; Lipase; Liquid substance; Lung; Marines; Measures; Mediterranean Sea; Mus; Nausea and Vomiting; Output; Pain; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Physiological; Plasma; Potassium; Proteins; Public Health; Puerto Rico; Pulmonary Edema; Research; Research Design; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Serum; Shark; Signs and Symptoms; Site; Sting Injury; Streptolysins; Syndrome; System; Tachycardia; Temperature; Thailand; Therapeutic; Therapeutic Intervention; Time; Tissues; United States Virgin Islands; Urine; VDAC1 gene; Venoms; Whole Blood; Work; base; cardiovascular collapse; clinically relevant; clinically significant; cytokine; design; effective therapy; evidence base; exposed human population; hyperkalemia; improved; in vivo; in vivo Model; insight; monocyte; peripheral blood; pressure; research study; response; response biomarker; standard of care; targeted treatment; time use

Box jellyfish envenomations account for myriad clinically significant sequelae, including debilitating sting-site pain and Irukandji syndrome, as well as in rare instances acute cardiovascular collapse and death, among residents and visitors to the U.S. coastal areas of Hawaii, Guam, Saipan, Florida, U.S. Virgin Islands and Puerto Rico. Cubozoan stings are also an increasing public health threat worldwide in tropical and subtropical areas of Australia, Indonesia, Thailand, Caribbean basin, Mediterranean Sea and Indian Ocean. Thus, there is an urgent need to better understand the pathogenesis of Irukandji syndrome, a potentially life-threatening sequelae with multi-systems symptoms and signs, suggestive of “cytokine storm” and “catecholamine surge”. Our long-term goal is to develop rapid diagnostics and effective treatments for the full spectrum of cubozoan envenomations. For the proposed research, our primary objective is to clarify the role of venom porins in the pathogenesis of Irukandji syndrome, by employing previously established in vitro and in vivo model systems. Our central hypothesis is that the cubozoan pore-forming proteins, or porins, induce a domino-type cascade of time-dependent pathophysiological effects on platelets, erythrocytes and peripheral blood mononuclear cells, including an initial dose-dependent release of biogenic amines and stored cytokines, which in turn causes a secondary induction of cytokine release from naïve leucocytes, as well as endothelial cells, that comprises Irukandji syndrome. A venom biochemist and an animal model expert will achieve the following specific aims. Aim 1. Compare the in vitro dose- and time-dependent effects of cubozoan whole venom and purified porin on human peripheral blood monocytes and platelets. Aim 2. Compare the in vivo dose-dependent effects of cubozoan whole venom and purified porin in piglets. Whole blood cell-based assays and a piglet animal model will be used to determine whether cubozoan porins cause specific systemic inflammatory effects and to track sequential physiological and biochemical responses in time-course experiments. Preliminary studies demonstrate that a central aspect of the pathogenesis of life- threatening jellyfish envenomation and Irukandji syndrome involves immune cell responses to cubozoan venom. Thus, this exploratory research project addresses a critical unmet need to better understand the pathophysiological role of cubozoan porin in order to develop rapid diagnostics and effective treatments.

箱形水母的毒液会导致无数具有临床意义的后遗症，包括蜇伤部位的衰弱 疼痛和伊鲁坎吉综合征，以及极少数情况下的急性心血管衰竭和死亡， 前往夏威夷、关岛、塞班岛、佛罗里达州、美属维尔京群岛等美国沿海地区的居民和游客 波多黎各立方体动物蜇伤也是全球热带和亚热带地区日益严重的公共卫生威胁。 澳大利亚、印度尼西亚、泰国、加勒比盆地、地中海和印度洋地区。 迫切需要更好地了解伊鲁坎吉综合征的发病机制，这是一种可能危及生命的疾病 具有多系统症状和体征的后遗症，提示“细胞因子风暴”和“儿茶酚胺激增”。 我们的长期目标是开发针对全谱立方体动物的快速诊断和有效治疗方法 对于拟议的研究，我们的主要目标是阐明毒液孔蛋白在毒液中的作用。 通过采用先前建立的体外和体内模型系统，研究伊鲁坎吉综合征的发病机制。 我们的中心假设是立方动物的成孔蛋白或孔蛋白诱导多米诺骨牌级联 对血小板、红细胞和外周血单核细胞的时间依赖性病理生理学影响， 包括生物胺和储存的细胞因子的初始剂量依赖性释放，这反过来又导致 二次诱导幼稚白细胞以及内皮细胞释放细胞因子，包括 伊鲁坎吉综合征。毒液生物化学家和动物模型专家将实现以下具体目标。 目标 1. 比较立方虫全毒液和纯化孔蛋白对体外剂量和时间依赖性的影响 人外周血单核细胞和血小板。 目标 2. 比较立方虫全毒液和纯化孔蛋白对仔猪的体内剂量依赖性效应。 基于全血细胞的测定和仔猪动物模型将用于确定立方体孔蛋白是否 引起特定的全身炎症反应并追踪连续的生理和生化反应 初步研究表明，生命发病机制的一个核心方面是 威胁性水母中毒和伊鲁坎吉综合征涉及免疫细胞对立方体动物的反应 因此，这个探索性研究项目解决了一个未满足的关键需求，即更好地了解毒液。 立方体孔蛋白的病理生理作用，以开发快速诊断和有效的治疗方法。