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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.

细胞外组蛋白引起微血管内皮细胞损伤的机制