Host Vascular Mechanism for Therapeutic Protection against Select Pathogens

针对特定病原体的治疗保护的宿主血管机制

• 批准号: 8923142
• 负责人: Joanne Chan
• 金额: $ 44.4万
• 依托单位: HAMPTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8923142
• 关键词: Achievement; Adverse effects; Angiogenic Factor; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Area; Bacillus anthracis; Biological; Biological Assay; Biology; Blood; Blood Vessels; Cardiovascular Physiology; Categories; Cell Line; Cell model; Cellular biology; Chemicals; Dengue Virus; Dose; Ebola virus; Edema; Embryo; Endothelial Cells; Endothelium; EphB4 Receptor; Extravasation; Fishes; Frankfurt-Marburg Syndrome Virus; Goals; Hemorrhagic Shock; Homologous Gene; Human body; Immune system; Infectious Agent; Injury; Institutes; Knowledge; Laboratories; Letters; Libraries; Ligands; Liquid substance; Lung; Lymphatic Endothelial Cells; Modeling; Modification; National Institute of Allergy and Infectious Disease; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase; Phospholipase C; Physiology; Play; Pseudomonas aeruginosa; Publications; Pulmonary Edema; Receptor Protein-Tyrosine Kinases; Regulation; Research; Resistance; Resources; Role; Signal Pathway; Signal Transduction; Surface; Symptoms; TIE-2 Receptor; Testing; Therapeutic; Tissues; Toxin; Trees; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular System; Vascular remodeling; Viral Hemorrhagic Fevers; Virus; Work; Zebrafish; angiogenesis; anthrax lethal factor; base; biodefense; chemical resource; clinically relevant; design; improved; in vitro Model; in vivo; inhibitor/antagonist; injured; interest; pathogen; receptor; resilience; respiratory; response; screening; small molecule; small molecule libraries; targeted treatment

PROJECT SUMMARY/ABSTRACT A number of NIAID Category A pathogens has developed mechanisms to injure the host through damaging the endothelial barrier to induce progressive vascular leakage. This leads to pulmonary edema and respiratory problems, hemorrhagic fever or shock-like symptoms. We hypothesize that improving vascular resilience and integrity could protect the host against a number of infectious agents. We will investigate the role of key regulators of endothelial integrity using the zebrafish model and in endothelial cell-based assays in the R21 phase of this study. Using anthrax lethal toxin as an inducer of vascular leakage, we will determine how altering host angiogenic signaling could improve endothelial barrier integrity and vascular function. In the R33 phase of this project, we will launch a large-scale chemical library screen, to identify positive hits and characterize their biological effects. We will take advantage of the current knowledge on 3 key angiogenic factors and their receptors, VEGF-A/VEGFR2, Angiopoietin 1/Tie2 and ephrinB2/EphB4, to establish reliable models for vascular integrity. These models will be used to identify small molecules that can improve vascular resilience as potential host-targeted therapies. We propose the following Specific Aims to be completed in the R21 phase: Aim 1. To establish the distinct roles of vascular ligands in comparison with anthrax lethal toxin (LT), in the regulation of permeability using zebrafish and endothelial cell models; Aim 2. To develop conditions for a small scale chemical compound screening using the zebrafish and endothelial cell models of vascular permeability through the use of NERCE chemical resources. Achievement of these Aims will be evaluated through 5 Milestones that would enable progression to the R33 phase of this project. The Aims for the R33 are as follows: Aim 3. To screen chemical libraries for compounds that can improve vascular integrity, R33, Y3-4; Aim 4. To evaluate the dose-response of selected positive compounds and determine whether structural alterations can improve vascular resilience while reducing adverse effects in the zebrafish model, as well as in blood and lymphatic endothelial cell leakage assays, R33, Y4-5. This project is designed to test a hypothesis on vascular protection as a host-targeted approach to pathogen challenge. We envisioned that positive results in the R21 phase will help define the screening strategy in the R33 phase of this project. Access to local chemical resources and expertise will expedite these efforts.

项目总结/摘要 许多NIAID A类病原体已经发展出通过破坏宿主细胞来伤害宿主的机制。 内皮屏障以诱导进行性血管渗漏。这会导致肺水肿和呼吸道感染。 问题、出血热或类似休克的症状。我们假设，改善血管弹性和 完整性可以保护宿主免受一些传染性病原体的侵害。我们将研究关键的作用 使用斑马鱼模型和R21中基于内皮细胞的测定中的内皮完整性调节剂 这个研究的阶段。使用炭疽致命毒素作为血管渗漏的诱导剂，我们将确定如何 改变宿主血管生成信号可以改善内皮屏障完整性和血管功能。在R33 在这个项目的第一阶段，我们将启动一个大规模的化学图书馆筛选，以确定积极的命中， 描述其生物学效应。我们将利用当前关于3个关键血管生成的知识 因子及其受体VEGF-A/VEGFR 2、Angiopoietin 1/Tie 2和ephrinB 2/EphB 4，以建立可靠的 血管完整性的模型。这些模型将用于识别可以改善血管的小分子， 作为潜在的宿主靶向疗法。我们建议以下具体目标在 R21阶段：目标1。与炭疽致死毒素相比，确定血管配体的不同作用 (LT)，在使用斑马鱼和内皮细胞模型的渗透性调节;目的2。发展病况 使用斑马鱼和血管内皮细胞模型进行小规模化合物筛选， 通过使用NERCE化学资源实现渗透性。将对这些目标的实现情况进行评估 这将使该项目进入R33阶段。的目标 R33如下：目标3。为了在化学文库中筛选能够改善血管完整性的化合物， R33，Y3-4;目标4。评价所选阳性化合物的剂量反应，并确定是否 结构改变可以改善血管弹性，同时减少斑马鱼模型的不良反应， 以及在血液和淋巴管内皮细胞渗漏测定中，R33，Y 4 -5。该项目旨在测试一个 血管保护作为病原体攻击宿主靶向方法的假说。我们设想， R21阶段的积极结果将有助于确定该项目R33阶段的筛选策略。 利用当地的化学资源和专门知识将加快这些努力。