Targeting Angiogenesis Pathways for Therapeutic Protection against Dengue

针对登革热治疗性保护的血管生成途径

• 批准号: 9223436
• 负责人: Sujan Shresta
• 金额: $ 27万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223436
• 关键词: ANGPT1 gene; Acute; Address; Agonist; Angiogenesis Pathway; Angiogenic Factor; Angiopoietin-2; Animal Model; Antibodies; Antibody-drug conjugates; Antiviral Agents; Blocking Antibodies; Blood Circulation; Blood Vessels; Blood capillaries; Capillary Permeability; Categories; Cell Culture Techniques; Cessation of life; Clinical Trials; Clinical Virology; Country; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Infection; Dengue Shock Syndrome; Dengue Vaccine; Dengue Virus; Development; Disease; Drug Targeting; Drug resistance; Early identification; Endothelial Cells; Extravasation; Foundations; Genotype; Goals; Growth Factor Receptors; Half-Life; Hemorrhage; Hour; Human; Immune response; Immunocompetent; Individual; Infection; Institution; Intercellular Junctions; KDR gene; Knowledge; Laboratories; Lead; Liquid substance; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Myeloid Cells; National Institute of Allergy and Infectious Disease; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Peptides; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Proteins; Publishing; RNA Viruses; Research; Role; Serotyping; Shock; Specificity; Syndrome; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Failure; Vascular Endothelial Growth Factors; Viral Hemorrhagic Fevers; Viral Load result; Virus; Virus Diseases; Virus Replication; base; capillary; hemorrhagic fever virus; improved; mouse model; novel; pathogen; small molecule; small molecule inhibitor; targeted treatment; type I interferon receptor; vaccine candidate; virus pathogenesis

The four serotypes of dengue virus (DENV) circulate in more than 100 countries, resulting in an estimated 90 million cases of disease. Among these persons with dengue disease are patients who develop acute capillary permeability resulting in internal fluid losses that if not corrected may lead to shock, hemorrhage, and death. The outcome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), is widely attributed to pathological pharmacologic mediators, as serious endothelial damage lasts for a matter of hours and is rapidly reversed. Early identification of individuals suffering from fluid loss should lead to appropriate fluid replacement that stabilizes the situation. Given the immense burden of symptomatic dengue in the world, it is not surprising that there are treatment failures—an estimated 20,000 persons die of dengue each year. Research in humans has revealed a pattern of angiogenic factors that accompany the shock syndrome. Among these are vascular endothelial growth factor (VEGF) and angiopoietin (Ang)- 1/Ang-2. A mouse model, developed in our laboratory, and widely used by others, recapitulates DHF/DSS, including capillary leakage leading to hemoconcentration, shock and death. As shown by our preliminary data, DENV-infected mice have elevated levels of VEGF and Ang-2, and treatment of mice with a small molecule drug that targets the VEGF pathway, which is involved in regulating endothelial cell stability and barrier function, protects mice from lethal DENV challenge. Based on these data, we hypothesize that targeting the VEGF and/or Ang-1/Ang-2 pathway will protect mice against DENV disease pathogenesis. To test this hypothesis, we propose the following Specific Aims: 1. To investigate whether inhibition of the VEGF pathway protects the host against DENV disease pathogenesis. 2. To investigate whether manipulation of the Ang-1/Ang-2 pathway protects the host against DENV disease pathogenesis.

登革热病毒的四种血清型在100多个国家传播，估计造成9 000万病例。在这些患有登革热疾病的人中，有发生急性毛细血管通透性的患者，导致内部液体损失，如果不纠正，可能导致休克、出血和死亡。结果，登革出血热/登革休克综合征（DHF/DSS），被广泛归因于病理药理学介质，因为严重的内皮损伤持续几个小时，并迅速逆转。早期识别患有液体流失的个体应导致适当的液体补充，以稳定情况。考虑到世界上有症状的登革热的巨大负担，治疗失败并不奇怪-估计每年有20，000人死于登革热。对人类的研究揭示了伴随休克综合征的血管生成因子的模式。其中包括血管内皮生长因子（VEGF）和血管生成素（Ang）-1/Ang-2。我们实验室开发的小鼠模型，被其他人广泛使用，概括了DHF/DSS，包括毛细血管渗漏导致血液浓缩，休克和死亡。如我们的初步数据所示，DENV感染的小鼠具有升高的VEGF和Ang-2水平，并且用靶向VEGF途径的小分子药物治疗小鼠，其参与调节内皮细胞稳定性和屏障功能，保护小鼠免受致命的DENV攻击。基于这些数据，我们假设靶向VEGF和/或Ang-1/Ang-2通路将保护小鼠免受DENV疾病发病机制的影响。为了验证这一假设，我们提出了以下具体目标：1。研究VEGF途径的抑制是否保护宿主免受DENV疾病发病机制的影响。2.研究Ang-1/Ang-2通路的操作是否保护宿主免受DENV疾病发病机制的影响。