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HDAC6 regulation of ICAM-1 expression and endothelial inflammatory signaling in sepsis

HDAC6 对脓毒症 ICAM-1 表达和内皮炎症信号的调节

基本信息

批准号：
10153866
负责人：
Jian Fu
金额：
$ 38.25万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153866
关键词：
Acetylation Binding Cell Adhesion Molecules Cell Communication Cell physiology Cessation of life Clinical Trials Cytoplasm Cytoskeleton Data Deacetylase Deacetylation Development Disease Endothelial Cells Endothelium Future Gene Expression HDAC4 gene HDAC6 gene Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intercellular adhesion molecule 1 JAK2 gene Knockout Mice Leukocytes Life Lung Mediating Mediator of activation protein Microtubule Stabilization Microtubules Morbidity - disease rate Multiple Organ Failure Nuclear Pathogenesis Play Regulation Reporting Role STAT1 gene STAT1 protein Sepsis Signal Pathway Signal Transduction Structure of parenchyma of lung Survival Rate TNF gene Testing Therapeutic Therapeutic Effect Tubulin Interaction alpha Tubulin experimental study inhibitor/antagonist knock-down mortality mouse model novel novel therapeutic intervention novel therapeutics prevent protective effect protein function transcription factor tumor vascular injury

项目摘要

Project Summary Sepsis is a life-threatening disease with high morbidity and mortality. New therapeutic strategies are urgently needed to treat this devastating disease. Uncontrolled endothelial inflammatory responses, which often leads to inflammatory vascular injury, contribute to the pathogenesis of multiple organ failure in sepsis. HDAC6, a histone deacetylase, has been reported to modulate nuclear and non-nuclear protein function through deacetylation. In this project, we will investigate HDAC6 regulation of endothelial inflammatory injury during sepsis. In our preliminary studies, we demonstrated that HDAC6 knockdown or selective HDAC6 inhibition prevented TNF-α induced endothelial ICAM-1 expression, which was associated with increased α-tubulin acetylation and reduced STAT1 activation. Furthermore, in mouse models of sepsis, HDAC6 inhibition blocked sepsis-induced lung ICAM-1 expression, induced α-tubulin acetylation, and suppressed STAT1 activation in lung tissues, which was associated with reduced lung inflammatory injury and increased survival rate. In the proposed studies, we will conduct a serial of experiments to assess the role of HDAC6 in sepsis-induced endothelial inflammatory responses, and to investigate therapeutic mechanisms of HDAC6 inhibition against endothelial inflammatory signaling in sepsis.

项目摘要脓毒症是一种高发病率和高死亡率的危及生命的疾病。新的治疗策略来治疗这种毁灭性的疾病不受控制的内皮炎性反应，这往往导致炎症性血管损伤，有助于发病机制，脓毒症中的多器官衰竭HDAC 6是一种组蛋白脱乙酰酶，据报道，核和非核蛋白通过脱乙酰化发挥作用。在这个项目中，我们将探讨HDAC 6对脓毒症时内皮炎性损伤调节作用。在我们的初步调查中研究中，我们证明HDAC 6敲低或选择性HDAC 6抑制可防止 TNF-α诱导内皮细胞ICAM-1的表达，这与α-微管蛋白的增加有关乙酰化和减少的STAT 1活化。此外，在败血症小鼠模型中，HDAC 6 抑制剂阻断脓毒症诱导的肺ICAM-1表达，诱导α-微管蛋白乙酰化，抑制肺组织中的STAT 1活化，这与肺组织中的炎性损伤和提高存活率。在拟议的研究中，我们将进行一系列评估HDAC 6在脓毒症诱导的内皮炎性细胞因子中的作用的实验反应，并研究HDAC 6抑制对内皮细胞的治疗机制，脓毒症中的炎症信号。