Endotoxin Neutralization by HDL-Mimetic Peptide

HDL 模拟肽中和内毒素

• 批准号: 7455901
• 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/7455901
• 关键词: Address; Advisory Committees; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoproteins A; Area; Atherosclerosis; Attenuated; Binding Proteins; Binding Sites; Blood Circulation; Cell Adhesion Molecules; Cell membrane; Cells; Cholesterol; Class; Clinical; Complex; Development; Economic Burden; Education; Endotoxins; Event; Glycolipids; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Health; Helix (Snails); High Density Lipoprotein Cholesterol; High Density Lipoproteins; Immune response; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferons; Interleukin-6; Intervention; Laboratories; Lipid A; Lipids; Lipopolysaccharides; Lipoproteins; Liver; Masks; Mediating; Membrane; Mentors; Microbe; Molecular; Morbidity - disease rate; Outcome; Parasites; Patients; Pattern; Peptides; Peripheral; Phospholipids; Plasma; Process; Property; Protein Binding; Proteins; Research; Research Personnel; Research Project Grants; Rodent Model; Role; Sepsis; Shapes; Source; Structure; Surface; Tandem Repeat Sequences; Testing; Therapeutic; Therapeutic Agents; Thinking; Toxic effect; Training; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States; Up-Regulation; Virus; abstracting; base; cytokine; design; ear helix; fungus; human TNF protein; in vivo; lipopolysaccharide-binding protein; member; mimetics; molecular shape; mortality; multidisciplinary; novel; particle; pre-beta high-density lipoprotein; prevent; programs; protective effect; receptor; response; reverse cholesterol transport; septic; skills; symposium

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）： 该提案的目的是为申请人提供以下领域的强化培训： 炎症和脂质学，并提高申请人的研究技能和专业知识，以促进他作为独立研究者的发展。候选人将接受既定研究人员和多学科咨询委员会的指导，并将开展教育计划（课程作业、会议和研讨会）和研究项目，研究 HDL 模拟肽减轻脂多糖 (LPS) 介导的败血症的保护机制。败血症是一个主要的健康问题。所有脓毒症病例中 25-30% 是由革兰氏阴性细菌 (GNB) 感染引起的。 LPS 是 GNB 外膜的一种成分，介导许多与脓毒症相关的毒性作用。结果表明 HDL 给药可能有效治疗脓毒症。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 表面的磷脂小叶中来实现的。这可能是由于 apo A-1（HDL 的主要蛋白质成分）和 LPS 的脂质 A 成分的分子形状互补而发生的。我们开发了一种新型肽，其设计基于 apo A-l 的结构。该肽 4F 是 A 类两亲性螺旋分子，具有 apo A-1 的许多抗动脉粥样硬化特性。 4F 的有益作用被认为是由于它能够调节 HDL 特性，包括形成前β HDL 样颗粒。我们观察到 4F 的分子形状与脂质 A 的分子形状互补。在本应用中，我们证明施用 4F 显着降低体外和体内 LPS 诱导的炎症细胞因子和粘附分子的激活。我们提出了新的假设，即载脂蛋白 A-1 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-l 的前β HDL 样颗粒的形成，从而增强 HDL 的 LPS 清除能力。这项研究对于了解 apo A-1 和 HDL 在 LPS 介导的脓毒症中的作用具有重要意义。它还将为开发 HDL 模拟肽作为对抗脓毒症/炎症的有效治疗剂提供依据。 （摘要完）