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：
10153818
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153818
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（申请人提供）：在美国，败血症每年影响超过 750,000 人，死亡率高达 30%。对于败血症和败血性休克患者，过度的中性粒细胞浸润是一个主要决定因素。脓毒症中的器官损伤，表明针对中性粒细胞运输是减少脓毒症的合理策略中性粒细胞和活化内皮细胞 (EC) 之间的相互作用是中性粒细胞浸润的关键调节因子。我们发现乳脂球-表皮生长因子-因子 8 (MFG-E8) 能够减少中性粒细胞的数量。在脓毒症动物的器官中，在脓毒症后施用重组人 MFG-E8 不仅可以减轻器官损伤，而且可以使动物的存活率加倍。我们还发现，冷诱导 RNA 结合蛋白 (CIRP) 在脓毒症中释放到循环中，并作为损伤相关分子模式 (DAMP) 发挥作用。我们已经证明，可以用 CIRP 中和抗体阻断 CIRP 活性。脓毒症后不仅可以抑制炎症，还可以显着提高脓毒症动物的存活率。最近，我们证明将重组鼠CIRP注射到健康小鼠体内会引起肺内EC激活和血管渗漏。该提案的重点是进一步阐明 MFG-E8 调节中性粒细胞运输和 CIRP 控制 EC 激活的机制，由于蛋白质的复杂性和难度，这些发现将指导治疗脓毒症的新疗法的设计和开发。基于生物治疗，我们专注于鉴定源自 MFG-E8 和 CIRP 的小分子寡肽，迄今为止，我们已经鉴定了两种候选肽：MSP68 和 C23。我们将分别从 MFG-E8 和 CIRP 中进一步评估它们治疗脓毒症的功效、半衰期和毒性。在本研究计划中，我们将解决以下三个关键问题：1）MFG-E8 如何抑制中性粒细胞活化。 2) CIRP 如何导致脓毒症中的血管 EC 激活和损伤？ 3) 我们能否制定针对中性粒细胞与 EC 相互作用的抗脓毒症策略？开发治疗脓毒症和脓毒性休克患者的创新疗法的新方向。