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：
9767826
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/9767826
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 Intercellular adhesion molecule 1 Interleukin-1 beta Interleukin-6 Internet Kidney Knock-out Knockout Mice Leukocytes Life Ligands Liver 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 Tissues Vascular Cell Adhesion Molecule-1 Wild Type Mouse base cecal ligation puncture chemokine clinical development cytokine effective therapy extracellular improved in vivo inhibitor/antagonist lung injury macrophage mortality neutralizing antibody neutrophil novel novel therapeutic intervention preclinical development public health relevance receptor septic

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：此R01项目的目标是研究冷诱导的机制 RNA结合蛋白（CIRP）增加败血症的严重程度并导致急性肺损伤（ALI）。败血症和阿里是致命，没有FDA批准的治疗。 CIRP是一种核蛋白，可以释放到败血症期间的循环，增加败血症的严重程度并导致ALI。我们发现CIRP 增加了一个新的嗜中性粒细胞的子集，其特征是细胞间粘合分子的表面表达 1（ICAM-1）。我们发现ICAM-1+中性粒细胞在化粪池的血液和肺中膨胀，但不是在CIRP淘汰小鼠中。我们进一步表明，用CIRP刺激足以诱导ICAM-1+ 中性粒细胞。我们第一次发现CIRP诱导的ICAM-1+中性粒细胞产生了更高的中性粒细胞外陷阱（网）的水平。基于这些新颖的发现，我们假设CIRP 诱导净形成ICAM-1+中性粒细胞在败血症中引起ALI。我们还表明C23，肽衍生从人CIRP中，剂量依赖性地抑制CIRP诱导的TNF-α释放，并抑制CIRP诱导 ICAM-1+中性粒细胞。这是我们进一步假设C23通过减少CIRP-的败血症诱导的ALI减弱诱导净形成中性粒细胞。我们将首先证明CIRP诱导净形成ICAM-1+ 嗜中性粒细胞及其在体内和体内的有害作用。接下来，我们将确定关键信号通路 CIRP诱导净形成ICAM-1+中性粒细胞。最后，我们将研究C23的能力抑制净形成的ICAM-1+中性粒细胞，降低败血症和ALI严重程度，并增加败血症的存活率。这些研究将提高我们对CIRP如何诱导净形成中性粒细胞引起的理解炎症和组织损伤，并支持C23的发展作为一种新的有效治疗方法败血症和ALI的患者。