MLL1 drives collaborative leukocyte-endothelial cell signaling and thrombosis after coronavirus infection

MLL1在冠状病毒感染后驱动白细胞-内皮细胞信号传导和血栓形成

基本信息

批准号：
10748433
负责人：
Nathaniel Parchment
金额：
$ 7.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-29 至 2025-09-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748433
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Address Adhesives Affect Anti-Inflammatory Agents Anticoagulants Automobile Driving Biological Assay COVID-19 Cell Adhesion Cell Adhesion Molecules Cell Line Cells Characteristics Chemotactic Factors Chromatin Coronavirus Coronavirus Infections DNA Data Analyses Development Disease E-Selectin Edema Endothelial Cells Endothelium Enzymes Epigenetic Process Event Experimental Designs Functional disorder Gene Expression Genes Genetic Goals Grant Hemorrhage Histone-Lysine N-Methyltransferase Histones ICAM1 gene Immune Immune response In Vitro Infection Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Influenza Injury Kidney Failure Lead Leukocytes Lung MLL gene Macrophage Mediating Mediation Mediator Methylation Mixed-Lineage Leukemia Modeling Modification Morbidity - disease rate Organ P-Selectin Patients Penetration Permeability Phenotype Physiological Play Pneumonia Prevention Production Promoter Regions Property Proteins RNA Interference Risk Role SARS-CoV-2 infection Scientist Secondary to Signal Transduction Source System Techniques Testing Thrombosis Thrombus Tissues Training Transgenic Mice Vascular Endothelium Venous Virus Diseases Work coronavirus treatment cytokine epigenetic regulation experimental study high risk in vivo inhibitor innovation interstitial monocyte mortality mouse model novel pharmacologic post SARS-CoV-2 infection pre-clinical prevent recruit response small molecule thrombotic complications tissue injury trafficking vascular bed vascular inflammation

项目摘要

Project Summary/Abstract Severe infection with the COVID-19 (severe acute respiratory syndrome coronavirus-2; SARS-CoV-2) results in numerous physiologic derangements including acute respiratory distress syndrome (ARDS) and renal failure. Injurious sequelae secondary to SARS-CoV-2 infection portend a significant morbidity and mortality and occur in part due to dysregulated host inflammatory response with resulting tissue injury. The hallmark of COVID- 19 pathophysiology is severe endotheliitis, intense inflammatory cell infiltrate and microthrombosis 9x more common than lethal influenza. Endothelial responsiveness and injury are thought to occur in response to inflammatory cytokine stimulation and cumulatively result in the loss of endothelial barrier function through dysregulation of endothelial cellular adhesion molecule (CAM) expression resulting in edema and inflammatory cell penetration of interstitial tissues which is seen in numerous vascular beds after SARS-CoV-2 infection. Additionally, endothelial cell activation further perpetuates the production of proinflammatory factors, and a prominent release of endothelial CAMs is observed and is postulated to function as a chemoattractant for immune cells such as MO/Mφs. Collectively, endothelial cells may play an integral role in the mediation of injurious sequelae in a post-coronavirus infected state. Accumulating evidence suggests that epigenetic regulation (covalent modifications to DNA and its associated proteins [e.g., histones]) through the activity of chromatin modifying enzymes (CMEs) in MO/Mφs is responsible for cellular phenotypic changes after coronavirus infection. We have identified a histone lysine methyltransferase, mixed lineage leukemia 1 (MLL1), as a mediator of cellular adhesion molecule induction following coronavirus infection. We hypothesize that MLL1 expression in endothelial cells drives endothelial activation and injury and works in concert with innate immune cells to drive tissue injury after coronavirus infection. This hypothesis will be investigated by two specific aims – 1) To examine how coronavirus-induced MLL1 alters CAM gene expression and endothelial phenotype. 2) To examine how MLL1 blockade alters thrombosis and endothelial permeability in response to coronavirus exposure in vitro and in vivo.

项目摘要/摘要 COVID-19的严重感染（严重的急性呼吸综合征冠状病毒-2； SARS-COV-2）导致许多生理发展，包括急性呼吸遇险综合征（ARDS）和肾脏失败。继发于SARS-COV-2感染继发的后遗症预示着显着的发病率和死亡率，部分原因是宿主炎症反应失调并导致组织损伤。 Covid-的标志 19病理生理学是严重的内皮炎，强烈的炎性细胞浸润和微栓塞9倍比致命的影响常见。人们认为内皮反应能力和伤害是为了响应炎性细胞因子刺激和累积地导致通过内皮细胞粘附分子（CAM）表达的失调，导致水肿和炎症 SARS-COV-2感染后在许多血管床中看到的间质时机的细胞渗透。此外，内皮细胞活化进一步使促炎因子的产生永久存在，A 观察到内皮凸轮的显着释放，并张贴以作为化学吸引剂的作用免疫细胞，例如mo/mφs。总体而言，内皮细胞可能在调解中起着不可或缺的作用后脊骨病毒感染状态下有害后遗症。积累的证据表明表观遗传调节（对DNA及其相关蛋白的共价修饰[例如，Hisonsones]）通过活性 MO/MφS中的染色质修饰酶（CME）负责细胞表型变化。冠状病毒感染。我们已经确定了组蛋白赖氨酸甲基转移酶，混合谱系白血病1（MLL1），作为冠状病毒感染后细胞粘合分子诱导的介质。我们假设MLL1 内皮细胞中的表达驱动内皮激活和损伤，并与先天免疫协同作用冠状病毒感染后驱动组织损伤的细胞。该假设将由两个具体目标进行研究 - 1）检查冠状病毒诱导的MLL1如何改变CAM基因表达和内皮表型。 2）检查MLL1如何避免改变血栓形成和内皮渗透性。体外和体内冠状病毒暴露。