Neutrophils in Sepsis: Role of CIRP

脓毒症中的中性粒细胞：CIRP 的作用

基本信息

批准号：
10197957
负责人：
Monowar Aziz
金额：
$ 33万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
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：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197957
关键词：
Acute Lung Injury Adoptive Transfer Antibodies Attenuated Binding Blood Blood Circulation Bone Marrow Cells Chromatin Development Disease Dose Endothelial Cells Environment FDA approved Goals Histology Human Immune response In Situ Nick-End Labeling In Vitro Infection Inflammation Inflammation Mediators Injections Injury Injury to Kidney Intercellular adhesion molecule 1 Interleukin-1 beta Interleukin-6 Internet Knock-out Knockout Mice Leukocytes Life Ligands Lung Macrophage-1 Antigen Measures Molecular Morbidity - disease rate Mouse Protein Mus Neutrophil Activation Nuclear Nuclear Protein PECAM1 gene Pathway interactions Patients Pattern Peptides Peroxidases Pharmaceutical Preparations Protein-arginine deiminase Proteins RNA-Binding Proteins Reactive Oxygen Species Recombinants Role Sepsis Serum Severities Signal Pathway Surface Syndrome TLR4 gene TNF gene Therapeutic Effect Time Vascular Cell Adhesion Molecule-1 Wild Type Mouse antibody transfer base cecal ligation puncture chemokine clinical development cytokine effective therapy extracellular improved in vivo inhibitor/antagonist liver injury lung injury macrophage mortality neutralizing antibody neutrophil novel novel therapeutic intervention preclinical development public health relevance receptor septic tissue injury

项目摘要

PROJECT DESCRIPTION: This R01 project's goal is to investigate the mechanism by which cold-inducible RNA-binding protein (CIRP) increases sepsis severity and causes acute lung injury (ALI). Sepsis and ALI are deadly and have no FDA-approved treatment. CIRP is a nuclear protein that can be released into the circulation during sepsis, increasing sepsis severity and causing ALI. We have discovered that CIRP increases a novel subset of neutrophils characterized by surface expression of intercellular adhesion molecule- 1 (ICAM-1). We found that ICAM-1+ neutrophils were expanded in the blood and lungs of septic mice, but not in CIRP knockout mice. We further showed that stimulation with CIRP was sufficient to induce ICAM-1+ neutrophils. For the first time, we discovered that CIRP-induced ICAM-1+ neutrophils produced much higher levels of neutrophil extracellular traps (NETs). Based on these novel findings, we hypothesize that CIRP induces NET-forming ICAM-1+ neutrophils to cause ALI in sepsis. We also showed that C23, a peptide derived from human CIRP, dose-dependently inhibits CIRP-induced release of TNF-α and inhibits CIRP induction of ICAM-1+ neutrophils. Thus, we further hypothesize that C23 attenuates sepsis-induced ALI by reducing CIRP- induced NET-forming neutrophils. We will first demonstrate CIRP's induction of NET-forming ICAM-1+ neutrophils and their deleterious effects, both in vitro and in vivo. Next, we will identify key signaling pathways through which CIRP induces NET-forming ICAM-1+ neutrophils. Finally, we will examine C23's ability to suppress NET-forming ICAM-1+ neutrophils, decrease sepsis and ALI severity, and increase sepsis survival. These studies will improve our understanding of how CIRP induces NET-forming neutrophils to cause inflammation and tissue injury and support the development of C23 as a new and effective treatment for patients with sepsis and ALI.

项目描述：该 R01 项目的目标是研究冷诱导的机制 RNA 结合蛋白 (CIRP) 会增加脓毒症的严重程度并导致急性肺损伤 (ALI)。 CIRP 是一种可释放到体内的核蛋白，具有致命性，且尚无 FDA 批准的治疗方法。败血症期间的循环，增加败血症的严重性并导致 ALI 我们发现 CIRP。增加以细胞间粘附分子表面表达为特征的新的中性粒细胞亚群- 1 (ICAM-1) 我们发现 ICAM-1+ 中性粒细胞在脓毒症小鼠的血液和肺部中扩增，但没有扩增。在 CIRP 敲除小鼠中，我们进一步表明 CIRP 刺激足以诱导 ICAM-1+。我们第一次发现 CIRP 诱导的 ICAM-1+ 中性粒细胞产生更高的水平。基于这些新发现，我们捕获了 CIRP。诱导形成 NET 的 ICAM-1+ 中性粒细胞导致脓毒症中的 ALI。我们还证明了 C23（一种肽衍生物质）。来自人 CIRP，剂量依赖性地抑制 CIRP 诱导的 TNF-α 释放，并抑制 CIRP 诱导因此，我们进一步研究 C23 通过减少 CIRP- 来减轻脓毒症引起的 ALI。我们将首先证明 CIRP 诱导形成 NET 的中性粒细胞。接下来，我们将确定关键的信号通路。 CIRP 通过它诱导 NET 形成 ICAM-1+ 中性粒细胞最后，我们将检查 C23 的能力。抑制形成 NET 的 ICAM-1+ 中性粒细胞，降低脓毒症和 ALI 严重程度，并增加脓毒症生存率。这些研究将提高我们对 CIRP 如何诱导 NET 形成的中性粒细胞引起的理解炎症和组织损伤，并支持 C23 的开发作为一种新的有效治疗方法脓毒症和急性肺损伤患者。