Novel Approaches to Maintaining Organ Function in Sepsis

 描述(申请人提供)：在美国，败血症每年影响超过75万人，死亡率高达30%。目前尚无有效的治疗败血症和感染性休克的方法。中性粒细胞过度渗透是脓毒症器官损伤的主要决定因素，提示以中性粒细胞转运为靶点是减少脓毒症的合理策略。 发病率和死亡率。中性粒细胞与激活的内皮细胞(ECs)之间的相互作用是中性粒细胞渗透的关键调节因素。我们发现乳脂球-表皮生长因子-8(MFG-E8)能够减少败血症动物器官中性粒细胞的数量。脓毒症后给予重组人MFG-E8不仅可减轻器官损伤，还可使脓毒症动物的存活率提高一倍。我们还发现，在脓毒症中，冷诱导的RNA结合蛋白(CIRP)被释放到循环中，并以损伤相关分子模式(DAMP)的形式发挥作用。我们已经证明，在脓毒症后用CIRP中和抗体阻断CIRP活性不仅可以抑制炎症，而且可以显著提高脓毒症动物的存活率。最近，我们已经证明，将重组小鼠CIRP注射到健康小鼠体内会导致EC激活和肺血管渗漏。这一建议的重点之一是进一步阐明MFG-E8‘S调控中性粒细胞转运和CIRP控制EC激活的机制。这些发现将指导设计和开发治疗脓毒症的新疗法。由于基于蛋白质的生物治疗药物开发的复杂性和难度，我们将重点放在鉴定MFG-E8和CIRP来源的小分子样寡肽上。到目前为止，我们已经鉴定出两个候选多肽MSP68和C23，分别来自MFG-E8和CIRP。我们将进一步评估它们治疗脓毒症的疗效、半衰期和毒性。在这项研究中，我们将解决以下三个关键问题：1)MFG-E8如何抑制脓毒症中中性粒细胞的激活和渗透？2)CIRP如何导致脓毒症中血管内皮细胞的激活和损伤？3)我们能否开发一种针对中性粒细胞-EC相互作用的抗脓毒症策略？这项研究将为开发治疗脓毒症和感染性休克患者的创新疗法开辟新的方向。

 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.