Sepsis and Mediators: the Role of MFG-E8-derived Peptides

败血症和介质：MFG-E8 衍生肽的作用

• 批准号: 8761161
• 负责人: PING WANG
• 金额: $ 34.54万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761161
• 关键词: Adhesions; Aftercare; Animal Model; Animals; Apoptotic; Area Under Curve; Attenuated; Bacterial Counts; Behavior; Binding; Biological Assay; Blood; Bone Marrow; Caring; Cause of Death; Cell Culture System; Cells; Chemotactic Factors; Chemotaxis; Complement; Complement 5a; DNA Sequence Rearrangement; Development; Disease; Dose; Drug Kinetics; Economic Burden; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Evaluation; Factor VIII; Family; Half-Life; Human; Infection; Infiltration; Inflammatory; Inflammatory Response; Injury; Integrins; Intensive Care Units; Knockout Mice; Lead; Leukotriene B4; Ligation; Liver; Lung; Maximum Tolerated Dose; Measures; Mediating; Mediator of activation protein; Medical; Molecular; Monomeric GTP-Binding Proteins; Multiple Organ Failure; Mus; Names; Neutrophil Infiltration; Organ; Patients; Peptides; Peritoneal; Peroxidases; Pharmaceutical Preparations; Property; Protein Kinase; Puncture procedure; Reaction; Reaction Time; Regulation; Research; Respiratory Burst; Role; Safety; Sepsis; Septic Shock; Series; Signal Transduction; Specificity; Structure; Surface Plasmon Resonance; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; attenuation; base; chemokine; cost; drug clearance; effective therapy; healthy volunteer; improved; innovation; killings; migration; milk fat globule; mortality; neutrophil; novel; novel therapeutics; prevent; protein structure; public health relevance; receptor; response; rho

DESCRIPTION (provided by applicant): Despite advances in the management of sepsis patients, a large number of those patients die from the ensuing septic shock and multiple organ failure. Thus, there is an urgent unmet medical need for a novel and effective therapy for sepsis. Excessive recruitment of activated neutrophils into various tissues is a major contributing factor for organ injury in sepsis. In the previous cycle of this project, we have demonstrated the beneficial effect of milk fat globule epidermal growth factor-factor VIII (MFG-E8) in reducing inflammatory responses and organ injury, and improving survival in an animal model of sepsis induced by cecal ligation and puncture (CLP). We have recently discovered a novel property of MFG-E8 in inhibiting the infiltration of activated neutrophils into tissues. By analyzing the proten structure of human MFG-E8 for its binding to integrins, we have screened a large number of human MFG-E8-derived peptides. We have identified a short peptide, named MSP68, which inhibited neutrophil adhesion and migration. In this renewal application, we will focus on further characterization of MSP68 in alleviating tissue injury in sepsis and the development of MSP68 as a new anti-sepsis therapy. Post-treatment with MSP68 significantly decreased the inflammatory responses and attenuated organ damage in sepsis mice induced by CLP. MSP68 treatment reduced the number of neutrophils infiltrating into the lungs and liver of sepsis mice. The ten-day survival of sepsis mice was markedly improved with MSP68 treatment. MSP68 had a direct effect on regulating neutrophil adhesion and chemotaxis. Using surface plasmon resonance (SPR) analysis, we further demonstrated that MSP68 bound to integrins directly. Based on these novel findings, we hypothesize that the human MFG-E8-derived peptide MSP68 inhibits neutrophil infiltration into tissues during sepsis, leading to the attenuation of tissue ijury and improvement in survival of sepsis animals. Accordingly, three specific aims are proposed: (1) to further investigate the role of MSP68 in inhibiting neutrophil infiltration in sepsis; (2) t determine the molecular mechanism responsible for such an inhibitory effect of MSP68; and (3) to evaluate the efficacy and safety of MSP68 as a therapeutic agent for sepsis. The proposed studies will lead to a new direction for the development of innovative therapeutics for patients with sepsis. Through this innovative research, it is expected that MSP68 will be developed as a novel drug to treat sepsis and septic shock.

描述（由申请人提供）：尽管败血症患者的治疗取得了进步，但仍有大量患者死于随后的败血性休克和多器官衰竭。因此，对于脓毒症的新颖且有效的疗法存在迫切的未满足的医疗需求。活化的中性粒细胞过度募集到各种组织中是脓毒症器官损伤的主要因素。在该项目的上一个周期中，我们已经证明了乳脂肪球表皮生长因子 VIII (MFG-E8) 在减少炎症反应和器官损伤方面的有益作用，并提高了盲肠结扎引起的脓毒症动物模型的生存率和穿刺（CLP）。我们最近发现了 MFG-E8 的一种新特性，可以抑制活化的中性粒细胞浸润到组织中。通过分析人MFG-E8与整合素结合的蛋白质结构，我们筛选了大量的人MFG-E8衍生肽。我们发现了一种短肽，命名为MSP68，它可以抑制中性粒细胞的粘附和迁移。在本次更新申请中，我们将重点关注 MSP68 在减轻脓毒症组织损伤方面的进一步表征，以及将 MSP68 开发为一种新的抗脓毒症疗法。 MSP68 后处理显着降低了 CLP 诱导的脓毒症小鼠的炎症反应并减轻了器官损伤。 MSP68 治疗减少了脓毒症小鼠肺部和肝脏中中性粒细胞的数量。 MSP68 治疗后脓毒症小鼠的十天存活率显着提高。 MSP68 对调节中性粒细胞粘附和趋化性有直接作用。使用表面等离子共振（SPR）分析，我们进一步证明MSP68直接与整合素结合。基于这些新发现，我们假设人 MFG-E8 衍生肽 MSP68 在脓毒症期间抑制中性粒细胞浸润到组织中，从而减轻组织损伤并提高脓毒症动物的存活率。据此，提出了三个具体目标：（1）进一步研究MSP68在脓毒症中抑制中性粒细胞浸润的作用； (2)确定MSP68产生这种抑制作用的分子机制； (3) 评估MSP68作为脓毒症治疗药物的有效性和安全性。拟议的研究将为脓毒症患者创新疗法的开发指明新方向。通过这项创新研究，预计MSP68将被开发为治疗脓毒症和脓毒性休克的新药。