Inflammatory Effects Of High Mobility Group Protein 1

高迁移率族蛋白 1 的炎症作用

• 批准号: 6993923
• 负责人: ANTHONY F. SUFFREDINI
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6993923
• 关键词: DNA binding protein; bacterial disease; clinical research; disease /disorder model; endotoxins; gene expression; genetic regulation; glycation; human subject; human tissue; immunogenetics; immunologic receptors; immunoregulation; inflammation; intermolecular interaction; microarray technology; protein structure function; recombinant proteins; tissue /cell culture; vascular endothelium

High mobility group protein (HMGB1) is a non-histone DNA binding protein that facilitates transcription. Recently, investigators have shown that HMGB1 has other roles that may be critical in the development of sepsis and septic shock. HMGB1 is released as a late mediator of sepsis (i.e., after 8 to 15 hours) from mononuclear cells stimulated with TNF, IL-1, or endotoxin. It is detected in the blood of septic mice and in septic patients and it worsens outcome when given to septic mice. It plays a role in migrating axons of neurons in the developing brain and it activates plasminogen. Some of the actions are through the RAGE receptor (receptor for advanced glycation products) which plays a role in chronic inflammation in diabetes. This novel axis of inflammation remains to be characterized in human sepsis. In order to study the target cells and contribution of HMGB1 to acute human inflammation, we are producing recombinant human HMGB1 in a bacterial expression system and are using the protein to study inflammatory responses in endothelium, respiratory epithelium, and mononuclear cells including alveolar macrophages. We are investigating conditions required for trhe release of biologically active HMGB1 from cells. In addition, we are developing biologically active peptide fragments of the intact molecule in order to study structure function relationships. Cell lines and migrating human cells from humans challenged with endotoxin will be studied for the expression of RAGE and their responses to HMGB1. HMGB1 will also be studied in blood and inflammatory lavage obtained from volunteers challenged with endotoxin (protocol 92-CC-0141). Oligonucleotide gene arrays will be used to study the inflammatory axis initiated by HMGB1 on target cells. These data should provide important new information regarding the role of HMGB1 in acute human inflammation to bacterial products.

高迁移率族蛋白（HMGB 1）是一种非组蛋白DNA结合蛋白，促进转录。最近，研究人员已经表明，HMGB 1在脓毒症和脓毒性休克的发展中可能具有其他关键作用。HMGB 1作为脓毒症的晚期介质释放（即，8至15小时后）从用TNF、IL-1或内毒素刺激的单核细胞中分离。它在脓毒症小鼠和脓毒症患者的血液中被检测到，当给予脓毒症小鼠时，它会改变结果。它在发育中的大脑中神经元的轴突迁移中起作用，并激活纤溶酶原。其中一些作用是通过β受体（晚期糖化产物受体），它在糖尿病的慢性炎症中发挥作用。这种新的炎症轴仍有待于在人类脓毒症中表征。为了研究HMGB 1对急性人类炎症的靶细胞和贡献，我们在细菌表达系统中产生重组人HMGB 1，并使用该蛋白研究内皮、呼吸道上皮和单核细胞（包括肺泡巨噬细胞）中的炎症反应。我们正在研究从细胞中释放具有生物活性的HMGB 1所需的条件。 此外，我们正在开发完整分子的生物活性肽片段，以研究结构功能关系。将研究细胞系和来自用内毒素挑战的人的迁移性人细胞的HMGB 1表达及其对HMGB 1的应答。还将在从用内毒素激发的志愿者获得的血液和炎症灌洗液中研究HMGB 1（方案92-CC-0141）。寡核苷酸基因阵列将用于研究HMGB 1在靶细胞上启动的炎症轴。这些数据应该提供关于HMGB 1在细菌产物的急性人类炎症中的作用的重要新信息。