Endotoxin Neutralization by HDL-Mimetic Peptide

HDL 模拟肽中和内毒素

• 批准号: 7133675
• 负责人: Himanshu Gupta
• 金额: $ 12.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-18 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7133675
• 关键词: apolipoproteins; biomimetics; cell membrane; clinical research; drug design /synthesis /production; drug screening /evaluation; endotoxins; gram negative bacteria; high density lipoproteins; human subject; inflammation; intermolecular interaction; laboratory rat; lipopolysaccharides; microorganism disease chemotherapy; peptides; pharmacokinetics; protein structure function; septicemia

DESCRIPTION (provided by applicant): The objectives of this proposal are to provide the applicant with intensive training in the areas of inflammation and lipidology and to advance applicant's research skills and expertise so as to facilitate his development as an independent investigator. The candidate will be mentored by established investigators and a multidisciplinary advisory committee and will pursue a program of education (coursework, conferences, and seminars) and a research project addressing the protective mechanisms by which an HDLmimetic peptide attenuates lipopolysaccharide (LPS)-mediated sepsis. Sepsis is a major health problem. 25- 30% of all cases of sepsis is due to gram negative bacterial (GNB) infection. LPS, a component of the outer membrane of GNB, mediates many of the toxic effects associated with sepsis. Results indicate that HDL administration may be effective in treating sepsis. However obtaining therapeutic quantities of the HDL is impractical. One mechanism by which HDL neutralizes LPS is thought to occur by insertion and masking of the lipid A domain of LPS into the phospholipid leaflet that covers the surface of HDL. This may occur due to complementary molecular shape of apo A-l (a major protein constituent of HDL) and the lipid A component of LPS. We have developed a novel peptide whose design is based on the structure of apo A-l. This peptide 4F is a class A amphipathic helical molecule that has many of the anti-atherosclerotic properties of apo A-l. Beneficial effects of 4F are thought to be due to its ability to modulate HDL properties including formation of pre-beta HDL like particles. We have observed that the molecular shape of 4F is complementary to that of lipid A. In this application, we demonstrate that administration of 4F significantly reduces LPS-induced activation of inflammatory cytokines and adhesion molecules both in-vitro and in-vivo. We propose the novel hypothesis that the apo A-l mimetic peptide 4F inhibits LPS induced inflammatory processes and will test whether this response is due to : i) Direct physical interaction between lipid A and 4F; ii) Indirect effects of 4F, by promoting the formation of apo A-l rich pre-beta HDL-like particles and thus enhancing the LPS scavenging capacity of HDL. This study will have important implications in understanding the role of apo A-l and HDL in LPS mediated sepsis. It will also provide a rationale for developing HDL-mimetic peptides as effective therapeutic agents against sepsis/inflammation. (End of Abstract)

描述（由申请人提供）： 本建议书的目的是为申请人提供下列领域的强化培训： 炎症和脂质学，并提高申请人的研究技能和专业知识，以促进他作为一个独立的研究者的发展。候选人将由已建立的研究人员和多学科咨询委员会指导，并将开展教育计划（课程，会议和研讨会）和研究项目，解决HDL模拟肽减弱脂多糖（LPS）介导的脓毒症的保护机制。败血症是一个主要的健康问题。25-30%的败血症病例是由于革兰氏阴性细菌（GNB）感染。LPS是GNB外膜的一种成分，介导了许多与脓毒症相关的毒性作用。结果表明，HDL给药可有效治疗脓毒症。然而，获得治疗量的HDL是不切实际的。HDL中和LPS的一种机制被认为是通过将LPS的脂质A结构域插入并掩蔽到覆盖HDL表面的磷脂小叶中而发生的。这可能是由于apo A-I（HDL的主要蛋白质成分）和LPS的脂质A组分的互补分子形状而发生的。我们已经开发了一种新的肽，其设计是基于载脂蛋白A-1的结构。该肽4F是A类两亲性螺旋分子，其具有apo A-I的许多抗动脉粥样硬化性质。 4F的有益作用被认为是由于其调节HDL性质的能力，包括前β HDL样颗粒的形成。我们已经观察到4F的分子形状与脂质A的分子形状互补。在这个应用中，我们证明了4F的管理显着减少LPS诱导的炎症细胞因子和粘附分子的激活在体外和体内。我们提出了新的假设，即apo A-I模拟肽4F抑制LPS诱导的炎症过程，并将测试这种反应是否是由于：i）脂质A和4F之间的直接物理相互作用; ii）4F的间接作用，通过促进富含apo A-I的前β HDL样颗粒的形成，从而增强HDL的LPS清除能力。本研究对了解载脂蛋白A-1和高密度脂蛋白在脂多糖介导的脓毒症中的作用具有重要意义。这也将为开发HDL模拟肽作为对抗脓毒症/炎症的有效治疗剂提供理论基础。 (End摘要）