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

基于脂质 A 的结构变体可预防革兰氏阴性脓毒症

• 批准号: 9753900
• 负责人: Robert K Ernst
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753900
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Acute; Age; Agonist; Antibiotics; Antisepsis; Bacteria; Binding; Blood; Caring; Cause of Death; Cessation of life; Clinical; Clinical Trials; Data; Drug Kinetics; Endotoxemia; Engineering; Enzymes; Evaluation; Event; Financial Hardship; Future; Goals; Gram-Negative Bacteria; Health system; Histologic; Hospitalization; Hospitals; Human; Imaging Techniques; Immune system; In Vitro; Infection; Inflammatory; International; Knowledge; Lead; Life; Lipid A; Lipopolysaccharides; Malignant neoplasm of prostate; Maps; Mass Spectrum Analysis; Medicare; Medicine; Membrane; Methods; Modeling; Modern Medicine; Modification; Multiple Organ Failure; Organ; Outcome; Patient-Focused Outcomes; Patients; Production; Research; Resolution; Rodent Model; Safety; Sepsis; Services; Shock; Signal Transduction; Structure; Structure-Activity Relationship; System; TLR2 gene; TLR4 gene; Techniques; Therapeutic; Therapeutic Uses; Tissues; Treatment Efficacy; United States; Vaccines; Variant; Work; base; combinatorial chemistry; cost; cytokine; cytokine release syndrome; design; efficacy testing; evidence base; gram-negative sepsis; improved; in vitro activity; in vivo; injured; insight; malignant breast neoplasm; method development; molecular modeling; novel; public health relevance; receptor; response; screening; symposium

 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.

 描述（由申请人提供）：脓毒症的公共定义，由2010年Merinoff研讨会上的国际专家聚会确定：“脓毒症是一种危及生命的疾病，当身体对感染的反应损伤其自身组织和器官时出现。脓毒症导致休克、多器官衰竭和死亡，特别是如果没有及早发现和及时治疗。败血症仍然是感染死亡的主要原因，尽管现代医学取得了进步，包括疫苗，抗生素和急性护理。“2011年，脓毒症占全国所有住院费用的5.2%（近110万美元）， 出院），也是向医疗保险收费最昂贵的疾病，占所有医疗保险费用的6.9%。每年死于败血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导致细胞因子风暴，这将健康的免疫系统（通常需要在血液传播感染的情况下进行干预）转化为患者的责任。革兰氏阴性菌引起的脓毒症部分依赖于细菌膜组分脂多糖（LPS）对Toll样受体4（TLR 4）的刺激。TLR 4刺激所需的LPS的最小组分是脂质A，LPS的膜锚组分。我们已经设计了初步的抗菌脂质A（ASLA）为基础的治疗方法，使用一个基本的，脂质A：TLR 4的结构-活性关系（SAR）作为指导。我们的假设是，使用合理的、基于证据的方法来改进抑制性脂质A分子的SAR，将导致有效设计的ASLA分子，其可以保护免受革兰氏阴性脓毒症，最终改善患者结局。为了证实这一假设，我们将：1）合理设计，表征和评估基于脂质A的治疗方法，2）采用高分辨率质谱技术来了解脂质A的最小结构组分，这些组分决定受体活性和功能。我们的研究将导致对内毒素血症的结构基础的深入理解，指导设计有效的革兰氏阴性脓毒症ASLA治疗剂。

项目成果

Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate.

• DOI: 10.1007/s13361-018-1897-y
• 发表时间: 2018-06
• 期刊: Journal of the American Society for Mass Spectrometry
• 影响因子: 3.2
• 作者: Oyler BL;Khan MM;Smith DF;Harberts EM;Kilgour DPA;Ernst RK;Cross AS;Goodlett DR
• 通讯作者: Goodlett DR

Species-Specific Endotoxin Stimulus Determines Toll-Like Receptor 4- and Caspase 11-Mediated Pathway Activation Characteristics.

• DOI: 10.1128/msystems.00306-21
• 发表时间: 2021-08-31
• 期刊: mSystems
• 影响因子: 6.4
• 作者: Ernst O;Khan MM;Oyler BL;Yoon SH;Sun J;Lin FY;Manes NP;MacKerell AD Jr;Fraser IDC;Ernst RK;Goodlett DR;Nita-Lazar A
• 通讯作者: Nita-Lazar A

Structural Elucidation of Intact Rough-Type Lipopolysaccharides using Field Asymmetric Ion Mobility Spectrometry and Kendrick Mass Defect Plots.

使用场不对称离子淌度谱和 Kendrick 质量缺陷图对完整粗糙型脂多糖进行结构解析。

• DOI: 10.1101/2023.06.21.545950
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Mikhael,Abanoub;Hardie,Darryl;Smith,Derek;Pětrošová,Helena;Ernst,RobertK;Goodlett,DavidR
• 通讯作者: Goodlett,DavidR