Therapeutic Interventions Against ANDV Induced Pathogenesis

针对 ANDV 诱发发病机制的治疗干预

基本信息

批准号：
8385518
负责人：
Erich R Mackow
金额：
$ 41.81万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385518
关键词：
Actins Acute Adherens Junction Altitude Andes Virus Angiopoietin-1 Animal Model Blocking Antibodies Blood Vessels Blood capillaries Capillary Permeability Cells Clinical Trials Cytolysis Cytoskeleton Dasatinib Disease Dissociation Edema Endothelial Cell Inhibitor Endothelial Cells Endothelium Equilibrium Extravasation FDA approved Figs - dietary Goals Hantavirus Hantavirus Pulmonary Syndrome Human Hyperbaric Oxygenation Hypoxia In Vitro Infection Joints Liquid substance Lung Mediating Mesocricetus auratus Modeling Onset of illness Pathogenesis Patients Peptides Permeability Pharmaceutical Preparations Phosphorylation Publishing Pulmonary Edema Receptor Signaling Research Personnel Respiratory Insufficiency Signal Pathway Signal Transduction Signaling Protein Symptoms TNF gene Therapeutic Therapeutic Intervention Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular Permeabilities Virus Diseases analog autocrine cadherin 5 capillary capillary bed cellular targeting inhibitor/antagonist kinase inhibitor lung hypoxia migrastatin mortality paracrine prevent receptor response sphingosine 1-phosphate src-Family Kinases translational study

项目摘要

DESCRIPTION (provided by applicant): Hantaviruses predominantly infect endothelial cells (ECs), and in the absence of cell lysis, cause diseases associated with dramatic increases in vascular permeability. Andes virus (ANDV) infection results in acute pulmonary edema and respiratory insufficiency termed hantavirus pulmonary syndrome (HPS). Vast pulmonary capillary beds provide an abundance of ECs for ANDV to infect and infection of ECs provides a primary means for ANDV to increase capillary permeability and cause edema. ANDV infection dramatically enhances EC permeability in response to VEGF and this is not observed following infection by non-pathogenic TULV or in response to TNF1. Our recent findings indicate that ANDV infection of ECs results in the hyperphosphorylation of VEGFR2, increased dissociation of VE-cadherin from AJs and increased paracellular permeability. We have also shown that ANDV induced permeability is inhibited by angiopoietin-1 (Ang-1), or sphingosine-1 phosphate (S1P) which antagonize VEGF directed permeability. These findings suggest that ANDV induced edema may be blocked by inhibiting VEGFR2 signaling pathways. ANDV infection of Syrian hamsters is the only animal model of hantavirus disease which closely mimics HPS, resulting in fatal acute pulmonary edema. This model permits the study of potential therapeutic compounds against ANDV disease and was developed by Jay Hooper the co- investigator on this proposal. In this joint proposal with Jay Hooper, we propose to apply our basic understanding of ANDV induced EC permeability to the Syrian Hamster model of hantavirus disease. Here we will evaluate the efficacy of compounds that enhance EC barrier functions for their ability to prevent HPS-like disease in Syrian hamsters.

描述（由申请人提供）：汉坦病毒主要感染内皮细胞（ECS），在没有细胞裂解的情况下，引起与血管渗透性急剧增加有关的疾病。安第斯山脉病毒（ANDV）感染导致急性肺水肿，呼吸道不足称为汉坦病毒肺综合征（HPS）。巨大的肺毛细血管床为ANDV提供了丰富的ECS感染和感染ECS，为ANDV提供了增加毛细血管渗透性并引起水肿的主要手段。 ANDV感染显着增强了对VEGF响应的EC渗透性，在非致病TULV感染或响应TNF1后，未观察到这一点。我们最近的发现表明，ECS的ANDV感染导致VEGFR2的高磷酸化，VE-钙粘着蛋白与AJS的分离增加并增加了细胞细胞渗透性。我们还表明，ANDV诱导的渗透性受到血管生成素-1（ANG-1）或鞘氨醇-1磷酸盐（S1P）的抑制，这些（S1P）拮抗了VEGF的定向渗透性。这些发现表明，ANDV诱导的水肿可能通过抑制VEGFR2信号通路阻塞。叙利亚仓鼠的ANDV感染是汉坦病毒疾病的唯一动物模型，该模型紧密模仿了HP，导致致命的急性肺水肿。该模型允许研究针对ANDV疾病的潜在治疗化合物，并由合伙人杰伊·胡珀（Jay Hooper）就该提案开发。在与杰伊·胡珀（Jay Hooper）的联合提案中，我们建议将我们对ANDV诱导的EC渗透性的基本理解应用于汉塔病毒疾病的叙利亚仓鼠模型。在这里，我们将评估化合物的功效，从而增强了EC屏障功能，以防止叙利亚仓鼠中的HPS样疾病。