MODULATION OF INNATE IMMUNE RESPONSES WITH SYNTHETIC LIPID A DERIVATIVES

用合成脂质 A 衍生物调节先天免疫反应

• 批准号: 8168857
• 负责人: Geert-Jan Boons
• 金额: $ 0.17万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-10 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168857
• 关键词: Accounting; Acylation; Asthma; Bacteria; Biological; Carbohydrates; Cell Wall; Clinical; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Fatty Acids; Funding; Gram-Negative Bacteria; Grant; Heterogeneity; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Institution; Knowledge; Lead; Lipid A; Lipids; Lipopolysaccharides; Malignant Neoplasms; Membrane; Molecular; Natural Immunity; Pattern; Phosphorylation; Research; Research Personnel; Resources; Septic Shock; Source; Structure; Structure-Activity Relationship; Symptoms; Therapeutic; Toxic effect; United States National Institutes of Health; Vaccine Adjuvant; Vertebral column; design; in vivo; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Evidence is emerging that innate immune responses can be exploited for therapeutic purposes such as the development of adjuvants for vaccines and the treatment of a wide range of diseases including asthma, infection, and cancer. An important concern of such therapies is, however, that over-activation of innate immunity may lead to the clinical symptoms of septic shock. Thus, an important issue for the design of safe immune modulators is a detailed knowledge of structure-activity relationships to harness beneficial effects without causing toxicity. Lipopolysaccharides (LPS) are structural components of the outer membrane of Gram-negative bacteria that offer great promise for the development of immuno-modulators. It has been demonstrated unequivocally that lipid A is the inflammation-inducing moiety of LPS. Recent structural studies have shown that the carbohydrate backbone, degree of phosphorylation, and fatty acid acylation patterns of lipid A vary considerably among bacterial species. These structural differences probably account for the highly variable in vivo and in vitro host responses to LPS. There is also some indication that structurally different lipid As may differentially induce proinflammatory responses. Heterogeneity in the structure of lipid A within a particular bacterial strain and possible contamination with other inflammatory components of the bacterial cell-wall complicates the use of either LPS or lipid A isolated from bacteria to dissect the molecular mechanisms responsible for the biological responses to specific lipid A molecules.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 越来越多的证据表明，先天免疫反应可用于治疗目的，例如开发疫苗佐剂以及治疗包括哮喘、感染和癌症在内的多种疾病。 然而，此类疗法的一个重要问题是先天免疫的过度激活可能导致感染性休克的临床症状。 因此，设计安全免疫调节剂的一个重要问题是详细了解结构-活性关系，以利用有益作用而不引起毒性。 脂多糖（LPS）是革兰氏阴性细菌外膜的结构成分，为免疫调节剂的开发提供了广阔的前景。 已明确证明脂质 A 是 LPS 的炎症诱导部分。最近的结构研究表明，脂质 A 的碳水化合物主链、磷酸化程度和脂肪酸酰化模式在细菌种类之间存在很大差异。这些结构差异可能解释了体内和体外宿主对脂多糖的反应的高度可变性。还有一些迹象表明，结构不同的脂质 As 可能会不同地诱导促炎反应。 特定细菌菌株内脂质 A 结构的异质性以及可能受到细菌细胞壁其他炎症成分的污染，使得使用从细菌中分离的 LPS 或脂质 A 来剖析负责对特定脂质的生物反应的分子机制变得复杂一个分子。