Protection Against Gram-Negative Sepsis Conferred by Lipid A-Based Structural Variants

 描述(由申请人提供)：国际专家在2010年梅里诺夫研讨会上对脓毒症的公开定义是：“败血症是一种当身体对感染的反应损害自身组织和器官时发生的危及生命的情况。脓毒症会导致休克、多器官衰竭和死亡，特别是如果不及早发现和及时治疗的话。尽管现代医学取得了进步，包括疫苗、抗生素和急性护理，但败血症仍然是感染死亡的主要原因。”2011年，脓毒症占全国所有住院费用的5.2%(近110万 医院出院)，也是向联邦医疗保险开出账单的最昂贵的疾病，占所有医疗保险成本的6.9%。每年死于脓毒症的人数超过前列腺癌、乳腺癌和艾滋病的总和。细菌在血液中的传播会导致细胞因子风暴，这会将健康的免疫系统转化为患者的负担。在血液传播感染的情况下，健康的免疫系统通常是干预所必需的。革兰氏阴性菌引起的脓毒症在一定程度上依赖于细菌膜成分脂多糖(LPS)对Toll样受体4(TLR4)的刺激。刺激TLR4所需的脂多糖的最小成分是脂蛋白A，它是脂多糖的膜锚定成分。我们以基本的类脂A：TLR4构效关系(SAR)为指导，设计了初步的抗败血症类脂A(ASLA)类药物。我们的假设是，使用合理的、循证的方法提炼SAR中的抑制性脂质A分子，将导致设计出有效的ASLA分子，从而预防革兰氏阴性脓毒症，最终改善患者的预后。为了证实这一假设，我们将：1)合理设计、表征和评估基于脂类A的疗法，以及2)使用高分辨率质谱学技术来了解决定受体活性和功能的脂类A的最小结构成分。我们的研究将有助于深入了解内毒素血症的结构基础，指导设计有效的ASLA治疗革兰氏阴性败血症的药物。

 DESCRIPTION (provided by applicant): The public definition of sepsis, as determined by a gathering of international experts at the Merinoff Symposium 2010 is: "Sepsis is a life threatening condition that arises when the body's response to an infection injures its own tissues and organs. Sepsis leads to shock, multiple organ failure and death especially if not recognized early and treated promptly. Sepsis remains the primary cause of death from infection despite advances in modern medicine, including vaccines, antibiotics and acute care." In 2011, sepsis represented 5.2% of the national costs for all hospitalizations (nearly 1.1 million hospital discharges) and was also the most expensive condition billed to Medicare, accounting for 6.9% of all Medicare costs. Deaths from sepsis outnumber those from prostate cancer, breast cancer, and AIDS, combined each year. Dissemination of bacteria in the blood results in a cytokine storm, which converts a healthy immune system, normally required to intervene in the case of a blood-borne infection, into a liability for the patient. Sepsis caused by Gram-negative bacteria is, in part, dependent on stimulation of Toll-like receptor 4 (TLR4) by the bacterial membrane component lipopolysaccharide (LPS). The minimal component of LPS necessary for TLR4 stimulation is lipid A, the membrane anchor component of LPS. We have designed preliminary anti-sepsis lipid A (ASLA) based therapeutics using a rudimentary, lipid A:TLR4 structure-activity relationship (SAR) as a guide. Our hypothesis is that refining the SAR for inhibitory lipid A molecules using a rational, evidence-based approach, will lead to effectivel designed ASLA molecules that can protect from Gram-negative sepsis, ultimately improving patient outcomes. To confirm this hypothesis we will: 1) rationally design, characterize, and evaluate lipid-A based therapeutics and 2) employ high resolution mass spectrometry techniques to understand the minimal structural components of lipid A that determine receptor activity and function. Our studies will lead to an advanced understanding of the structural basis for endotoxemia, instructing the design of efficacious ASLA therapeutics for Gram-negative sepsis.