Novel Approaches to Maintaining Organ Function in Sepsis

维持脓毒症器官功能的新方法

基本信息

批准号：
9698963
负责人：
PING WANG
金额：
$ 51.18万
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：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9698963
关键词：
Address Affect American Animals Antisepsis Attenuated Biological Response Modifier Therapy Blood Circulation Blood Vessels Cause of Death Cell Communication Cells Development Endothelial Cells Epidermal Growth Factor Extravasation Germ Grant Half-Life Health Expenditures Human Inflammation Inflammatory Response Injections Injury Leukocytes Lung Malignant Neoplasms Molecular Morbidity - disease rate Mus Neutrophil Activation Neutrophil Infiltration Oligopeptides Organ Patients Pattern Peptides Pharmaceutical Preparations Proteins RNA-Binding Proteins Recombinants Regulation Research Research Support Sepsis Septic Shock Therapeutic Therapeutic Agents Toxic effect Vascular Endothelial Cell base cost design effective therapy improved innovation milk fat globule mortality neutralizing antibody neutrophil novel strategies novel therapeutics organ injury prevent programs public health relevance septic septic patients small molecule trafficking

项目摘要

DESCRIPTION (provided by applicant): In the US, sepsis affects more than 750,000 people annually, with a mortality rate as high as 30%. There is still no effective therapy for patients wih sepsis and septic shock. Excessive neutrophil infiltration is a major determinant of organ injury in sepsis, suggesting that targeting neutrophil trafficking is a rational strategy to reduce sepsis morbidity and mortality. The interaction between neutrophils and activated endothelial cells (ECs) is a key regulator of neutrophil infiltration. We have discovered that milk fat globule-epidermal growth factor-factor 8 (MFG-E8) is able to reduce the number of neutrophils in organs of septic animals. Administration of recombinant human MFG-E8 after sepsis not only attenuated organ damage, but also doubled the survival of septic animals. We have also discovered that cold-inducible RNA-binding protein (CIRP) is released into the circulation in sepsis and functions as a damage-associated molecular pattern (DAMP). We have demonstrated that blocking CIRP activities with CIRP-neutralizing antibodies after sepsis not only inhibited inflammation, but also markedly improved the survival of septic animals. Recently, we have demonstrated that injection of recombinant murine CIRP into healthy mice caused EC activation and vascular leakage in the lungs. One focus of this proposal is to further elucidate the mechanisms responsible for MFG-E8's regulation of neutrophil trafficking and CIRP's control of EC activation. These findings will guide the design and development of new therapeutics for treating sepsis. Due to the complexity and difficulty in developing protein-based biotherapeutics, we focused on identifying small molecule-like oligopeptides derived from MFG-E8 and CIRP. To date, we have identified two candidate peptides, MSP68 and C23, derived from MFG-E8 and CIRP, respectively. We will further evaluate their efficacy, half-life and toxicity for treating sepsis. In this research program, we will address the following three key questions: 1) How does MFG-E8 inhibit neutrophil activation and infiltration in sepsis? 2) How does CIRP cause vascular EC activation and injury in sepsis? 3) Can we develop an anti-sepsis strategy targeting the neutrophil-EC interaction? The proposed research will lead to a new direction for the development of innovative therapeutics to treat patients suffering from sepsis and septic shock.

描述（由申请人证明）：在美国，败血症超过750,000人，死亡率是患者的有效治疗，对败血症和败血性休克过度浸润。贩运是减少败血症的评级策略发病率和死亡率。化粪池动物的器官。 AA的Ntibies不抑制重组CIRP的炎症，并在肺部引起的血管渗漏从MFG-E8和CIRP衍生的小分子样寡肽。三个关键问题：1）MFG-E8如何抑制败血症中的中性粒细胞激活？开发创新的治疗剂来治疗患有败血症和隔离休克的患者。