HDAC6 regulation of myeloid cell responses in sepsis

HDAC6 对脓毒症中骨髓细胞反应的调节

基本信息

批准号：
10490865
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：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10490865
关键词：
Acetylation Affect Apoptosis Bacteria Cell Differentiation process Cell Survival Cell physiology Cells Clinical Trials Cytoskeleton Deacetylation Development Disease Endotoxins Epigenetic Process Failure Functional disorder Future Generations Genetic Transcription HDAC6 gene Health Histone Deacetylase IRF1 gene Immune Immune System Diseases Immune response Infection Inflammation Inflammatory Interferons Life Mediating Mediator of activation protein Metabolic Microtubule Stabilization Microtubules Modification Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Pathway interactions Phenotype Play Regulation Reporting Role STAT1 gene Sepsis Signal Transduction Suppressor-Effector T-Lymphocytes Survival Rate Testing Therapeutic Therapeutic Effect alpha Tubulin hematopoietic stem cell expansion immunoregulation improved macrophage mortality mouse model novel progenitor response septic stem cells transcriptomics

项目摘要

Project Summary Sepsis is a life-threatening disease caused by dysregulated host responses to infection. Sepsis remains a major health problem worldwide with high mortality. Myeloid cell responses such as endotoxin tolerance, epigenetic modification, metabolic failure, and apoptosis are profoundly affected in sepsis, which leads to systemic dysfunction of immune cells and progenitor cells. The regulation of myeloid cell responses in sepsis remains largely unknown. The histone deacetylase HDAC6 regulates a variety of cellular responses. However, HDAC6 regulation of myeloid cell responses in sepsis has not been investigated. Our preliminary studies indicate that HDAC6 is a key mediator of cell signaling in myeloid cells. Myeloid-specific HDAC6 deletion reduces the mortality in septic mice. Furthermore, selective HDAC6 inhibition can modulate myeloid cell responses in the mouse models of sepsis. In the proposed studies, we will test the hypothesis that HDAC6 activation mediates myeloid cell dysfunction in sepsis, and HDAC6 inhibition could improve myeloid cell function and survival rate in sepsis.

项目摘要败血症是一种威胁生命的疾病，由宿主对感染的反应失调。败血症在全球范围内仍然是一个主要的健康问题，死亡率很高。髓样细胞反应，例如内毒素的耐受性，表观遗传修饰，代谢衰竭和凋亡是深刻的在败血症中受到影响，导致免疫细胞和祖细胞的全身功能障碍。这败血症中髓样细胞反应的调节仍然很大未知。组蛋白脱乙酰基酶 HDAC6调节各种细胞反应。但是，HDAC6调节髓样细胞败血症的反应尚未得到研究。我们的初步研究表明HDAC6是一个髓样细胞中细胞信号的关键介体。粒细胞特异性的HDAC6删除可减少化粪池的死亡率。此外，选择性HDAC6抑制可以调节髓样细胞败血症的小鼠模型中的响应。在拟议的研究中，我们将检验假设 HDAC6激活介导败血症中的髓样细胞功能障碍，HDAC6抑制作用可能提高败血症中的髓样细胞功能和存活率。