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: 8391488
• 负责人: Joanne Chan
• 金额: $ 24.67万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-02 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391488
• 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; Screening procedure; 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; small molecule; small molecule libraries

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Pathogens induce specific effects while disrupting host physiology. Although activation of the host immune system is an important step, many infectious agents alter cardiovascular function through damage to endothelial cells. When this occurs, the patient suffers from respiratory problems because the lungs are filled with fluid that leaked out o the blood vessels. Endothelial cells line the entire vascular tree in the human body, covering approximately 100 m2 of surface area and providing the largest host tissue for pathogen action. By understanding how to improve vascular integrity and identifying drugs that can induce endothelial resilience, these drugs might be widely protective against a number of biodefense-relevant pathogens.

描述（由申请人提供）：许多 NIAID A 类病原体已形成通过破坏内皮屏障以诱导进行性血管渗漏来伤害宿主的机制。这会导致肺水肿和呼吸系统问题、出血热或休克样症状。我们假设提高血管的弹性和完整性可以保护宿主免受多种传染源的侵害。我们将使用斑马鱼模型和本研究 R21 阶段基于内皮细胞的测定来研究内皮完整性关键调节因子的作用。使用炭疽致死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。在该项目的 R33 阶段，我们将启动大规模化学库筛选，以识别积极的命中并表征其生物效应。我们将利用目前对 3 个关键血管生成因子及其受体 VEGF-A/VEGFR2、血管生成素 1/Tie2 和 ephrinB2/EphB4 的了解，建立可靠的血管完整性模型。这些模型将用于识别可以提高血管弹性的小分子，作为潜在的宿主靶向疗法。我们建议在 R21 阶段完成以下具体目标： 目标 1. 使用斑马鱼和内皮细胞模型确定血管配体与炭疽致死毒素 (LT) 相比在通透性调节中的独特作用；目标 2. 通过使用 NERCE 化学资源，利用血管通透性的斑马鱼和内皮细胞模型来开发小规模化合物筛选的条件。这些目标的实现将通过 5 个里程碑进行评估，这些里程碑将使该项目能够进入 R33 阶段。 R33 的目标如下： 目标 3. 筛选化学库中可以改善血管完整性的化合物，R33、Y3-4；目标 4. 评估所选阳性化合物的剂量反应，并确定结构改变是否可以改善血管弹性，同时减少斑马鱼模型以及血液和淋巴内皮细胞渗漏测定中的不良影响，R33，Y4-5。该项目旨在测试血管保护作为针对病原体攻击的宿主靶向方法的假设。我们预计 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。获得当地化学资源和专业知识将加快这些努力。 公共卫生相关性：病原体在破坏宿主生理机能的同时会产生特定的影响。虽然宿主免疫系统的激活是重要的一步，但许多感染因子通过损害内皮细胞来改变心血管功能。当这种情况发生时，患者会出现呼吸问题，因为肺部充满了从血管漏出的液体。内皮细胞排列在人体内的整个血管树上，覆盖约 100 平方米的表面积，并为病原体的作用提供最大的宿主组织。通过了解如何改善血管完整性并识别可以诱导内皮弹性的药物，这些药物可能可以广泛地预防许多与生物防御相关的病原体。