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Mechanisms of microvascular endothelial cell injury caused by extracellular histones

细胞外组蛋白致微血管内皮细胞损伤的机制

基本信息

批准号：
10679043
负责人：
Anna Birukova
金额：
$ 46.56万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679043
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Affect Agonist Animal Genetics Animal Model Area Bacteria Binding Biochemical Blood Vessels Brain Edema Cause of Death Cell Death Cell Death Induction Cell Nucleus Cells Cessation of life Circulation Complex DNA-Binding Proteins Data Development Dose Endothelial Cells Endothelium Failure Fostering Functional disorder Genetic Models Health Histones Immune Infection Inflammation Inflammatory Injury Investigation Knowledge Lipids Lung Mediating Membrane Lipids Membrane Microdomains Microcirculation Modeling Molecular Molecular Target Multiple Organ Failure NF-kappa B Necrosis Nuclear Operative Surgical Procedures Organ Organ failure Particulate Matter Pathologic Pathway interactions Patients Pattern Peptides Permeability Pilot Projects Play Prognostic Factor Publishing Pulmonary Edema Receptor Cell Regulation Sepsis Severities Signal Transduction Staphylococcus aureus Stimulus Surface Syndrome TNFRSF10B gene Testing Tissues Toxin Trauma Traumatic injury Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vascular Permeabilities cell injury endothelial dysfunction extracellular imaging approach improved injured insight lung injury mortality novel novel therapeutic intervention pathogenic bacteria receptor recruit respiratory response scavenger receptor tissue injury trafficking translational study vascular inflammation

项目摘要

Mechanisms of microvascular endothelial cell injury caused by extracellular histones Abstract Despite the recent progress towards understanding of the basis of increased vascular permeability and inflammation caused by circulating vasoactive peptides, lipids, and exogenous agents (bacteria, toxins, particulate matter), the impact of intracellular compounds released by injured tissues and known as danger- associated molecular patterns (DAMPs) on severity of ongoing acute respiratory syndrome caused by sepsis or traumatic injury remain poorly understood, and molecular mechanisms underlying deleterious effects of DAMPs warrant further investigations. This translational study will investigate effects of nucleus-associated DAMPs, histones, on vascular endothelial function and test a new hypothetical mechanism by which circulating histones target lung microvascular endothelium and worsen lung injury. The central hypothesis tested in this application is that circulating histones elevated during acute lung injury, sepsis, trauma, severe inflammation, or major surgery target vascular endothelium and contribute to overall vascular dysfunction, organ damage and mortality. This may be achieved through: 1) histone-induced engagement of scavenger receptor cluster of differentiation 36 (CD36) leading to propagation of endothelial inflammation and barrier dysfunction; and 2) CD36-induced activation of death signaling by circulating histones contributing to augmentation of ongoing endothelial dysfunction and lung injury. The proposed study may have a broader impact on the other aspects of vascular responses to inflammatory or pro-angiogenic stimuli. Proposed studies will provide mechanistic insights offering better understanding of factors that define severity of sepsis and trauma. These studies may lead to identification of molecular targets and developing new therapeutic approaches to mitigate such deleterious effects of circulating DAMPs.

细胞外组蛋白致微血管内皮细胞损伤的机制摘要尽管最近在理解血管通透性增加和由循环血管活性多肽、脂类和外源性物质(细菌、毒素、颗粒物)，损伤组织释放的细胞内化合物的影响，称为危险- 脓毒症所致持续急性呼吸综合征严重程度的相关分子模式(DAMP) 或创伤性损伤仍然知之甚少，而潜在的有害影响的分子机制潮湿的情况需要进一步调查。这项翻译研究将调查核相关的影响组蛋白对血管内皮细胞功能的抑制作用并测试一种新的假想的循环机制组蛋白以肺微血管内皮细胞为靶点，加重肺损伤。在这里检验的中心假说应用是在急性肺损伤、脓毒症、创伤、严重炎症、或大手术以血管内皮细胞为靶点，并导致整体血管功能障碍、器官损害和死亡率。这可能是通过：1)组蛋白诱导清道夫受体簇参与分化36(CD36)导致内皮细胞炎症和屏障功能障碍的扩散；以及2) CD36通过循环组蛋白激活死亡信号，有助于增强正在进行的内皮功能障碍和肺损伤。拟议的研究可能会对其他方面产生更广泛的影响血管对炎性或促血管生成刺激的反应。拟议的研究将提供机械性的洞察力提供更好地理解定义脓毒症和创伤严重程度的因素。这些研究可能导致识别分子靶点并开发新的治疗方法来缓解这种情况循环潮湿的有害影响。