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

基本信息

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
项目类别：
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

项目摘要

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 (DENV) 的四种血清型在 100 多个国家/地区进行了审查，估计导致 9000 万登革热病例，其中一些患者出现急性毛细血管通透性，导致体内液体流失，如果不加以纠正，可能会导致这种情况。导致休克、出血和死亡的结果，登革出血热/登革热休克综合征 (DHF/DSS)，被广泛归因于病理药理介质，如严重的内皮损伤会持续几个小时，并且会迅速逆转。早期识别出患有液体流失的个体应该进行适当的液体补充，以稳定局势，考虑到世界范围内有症状的登革热造成的巨大负担，这并不奇怪。治疗失败——估计每年有 20,000 人死于登革热，人类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是我们实验室开发的一种小鼠模型，它概括了DHF/DSS，包括导致血液浓缩、休克和死亡的毛细血管渗漏，如我们的初步数据所示。 - 感染小鼠的 VEGF 和 Ang-2 水平升高，用靶向 VEGF 通路的小分子药物治疗小鼠，该通路参与调节内皮细胞稳定性和屏障根据这些数据，我们发现靶向 VEGF 和/或 Ang-1/Ang-2 通路将保护小鼠免受 DENV 疾病的发病机制的影响。为了检验这一假设，我们提出了以下具体目标。： 1. 研究抑制 VEGF 通路是否可以保护宿主免受 DENV 疾病发病机制的影响。 2. 研究调控 Ang-1/Ang-2 通路是否可以保护宿主免受 DENV 疾病发病机制的影响。