Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease

了解抗载脂蛋白 A-I 抗体在动脉粥样硬化性心血管疾病中的作用

• 批准号: 10112952
• 负责人: Vincent Joseph Venditto
• 金额: $ 26.39万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112952
• 关键词: Address; Anti-Inflammatory Agents; Antibodies; Antibody Response; Antibody Therapy; Antigen-Antibody Complex; Antigens; Antiinflammatory Effect; Apolipoprotein A-I; Arterial Fatty Streak; Atherosclerosis; Autoantibodies; Autoantigens; Biology; Blood Circulation; Cardiovascular Diseases; Cells; Centers of Research Excellence; Cessation of life; Characteristics; Chemicals; Consumption; Coronary Arteriosclerosis; Coupled; Data; Development; Disease Progression; Epitopes; Evaluation; Exhibits; Fc Receptor; Female; Foundations; Goals; Health; High Density Lipoproteins; Human; IgG1; IgG4; Immune; Immune response; Immunization; Immunoglobulin G; Immunologics; Immunotherapy; Investigation; Kentucky; Laboratories; Link; Mass Spectrum Analysis; Mediating; Mission; Modeling; Molecular; Mus; Myocardial Infarction; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Peptide antibodies; Peptides; Pharmacologic Substance; Phenotype; Prevention; Procedures; Proteins; Reporting; Research; Role; Specificity; Structure; TLR4 gene; Testing; Universities; Work; athero susceptible; base; biophysical properties; cancer immunotherapy; cardiovascular disorder risk; functional outcomes; human subject; immunogenic; immunogenicity; immunomodulatory therapies; immunoregulation; improved; in silico; in vitro Assay; in vivo; innovation; insight; macrophage; male; mouse model; novel; novel therapeutic intervention; polarized cell; receptor; success; therapeutic development; treatment strategy; western diet

PROJECT SUMMARY / ABSTRACT – PROJECT 4 The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediated pathogenesis of cardiovascular disease (CVD). Detailed characterization of the antigen, epitope specificity, antibody subclass and receptor engagement will enhance the understanding of CVD and guide therapeutic development. One target of IgG antibody induction in patients is apolipoprotein A-I (ApoA-I), the major protein of high density lipoprotein (HDL). Although anti-ApoA-I antibodies have been identified in mice and human subjects, the role of these antibodies have not been elucidated. Furthermore, the immunologic impact of antibodies bound to ApoA-I in an immune complex (ApoA-I/IgG ICs) is unclear. The long-term goal is to develop novel peptide and antibody therapeutics based on mechanistic insight from mice, to reduce the burden of CVD in patients. To achieve this goal, the overall objectives of this proposal build from our observations in human subjects to characterize the molecular components of the anti-ApoA-I antibody response in mice and correlate their characteristics with cellular interactions, functional outcomes and atherosclerosis progression. The hypothesis is that anti-ApoA-I antibodies exhibit both pro- and anti-inflammatory effects depending on the antibody characteristics (i.e. subclass, epitope specificity, Fc receptor interaction) leading to exacerbation or suppression of atherosclerosis. The rationale for this proposed research is that understanding one component of the immune response associated with CVD will promote improved patient outcomes through novel therapeutic strategies. Encouraged by strong preliminary data, this hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of antibodies targeting peptide epitopes derived from ApoA-I; and 2) Determine if ApoA-I/IgG ICs mediate an anti-inflammatory phenotype by engaging with the inhibitory Fc receptor using in vitro assays and in vivo studies in atherosusceptible mouse models. In the first aim, a structure immunogenicity relationship will be generated by correlating in silico modeling, biophysical characterization and immunogenicity studies of known peptide epitopes derived from ApoA-I. These data will be correlated with antibody profiles and subclass composition of the antibody response toward ApoA-I. In the second aim, the mechanistic impact of anti-ApoA-I antibodies will be determined by characterizing cell polarization in the presence of specific anti-ApoA-I profiles and inducing antibody profiles in atherosusceptible mice lacking Fc receptors. The innovation and significance of the proposed work is driven by the novel immunomodulation strategies that will improve our understanding of antibody-mediated immune responses, which will guide continued efforts to develop novel immunotherapies through coordination with the CPRI COBRE, to decrease the burden of CVD in patients.

项目摘要 /摘要 - 项目4 动脉粥样硬化斑块中自身抗原的鉴定促使对抗体介导的研究 心血管疾病（CVD）的发病机理。抗原，表位特异性的详细表征， 抗体亚类和受体参与将增强对CVD和指导治疗的理解 发展。患者IgG抗体的一个靶标是载脂蛋白A-I（ApoA-I），这是主要蛋白 高密度脂蛋白（HDL）。尽管在小鼠和人类受试者中已经鉴定出抗APOA-1抗体，但 这些抗体的作用尚未阐明。此外，抗体结合的免疫学影响 在免疫复合物（APOA-I/IgG ICS）中对ApoA-I尚不清楚。长期目标是开发新型肽 和基于小鼠的机械洞察力的抗体疗法，以减少患者CVD的燃烧。到 实现这一目标，这项提案的总体目标是从我们在人类对象中的观察结果到 表征抗APOA-I抗体反应的分子成分，并将其相关 具有细胞相互作用，功能结局和动脉粥样硬化进展的特征。假设 是抗Apoa-I抗体表现出促抗体和抗炎作用，具体取决于抗体 特征（即子类，表位特异性，FC受体相互作用）导致加剧或抑制 动脉粥样硬化。这项拟议研究的理由是了解免疫的一个组成部分 与CVD相关的反应将通过新颖的治疗策略促进改善患者的结果。 在强大的初步数据的鼓励下，该假设将通过两个特定目的进行检验：1）阐明 靶向肽表位的抗体的分子成分和功能意义。 apoa-i; 2）确定apoa-i/igG是否通过与 在动脉粥样硬化小鼠模型中使用体外测定和体内研究的抑制性FC受体。在第一个 目的，结构免疫性关系将通过在生物物理中的硅物质建模中相关联产生 源自ApoA-I的已知肽表位的表征和免疫原性研究。这些数据将是 与抗体对ApoA-I的抗体谱和亚类组成相关。在 第二个目的，抗APOA-I抗体的机械影响将通过表征细胞来确定 在特定的抗Apoa-I轮廓和诱导的抗体谱的情况下极化 缺乏FC受体的小鼠。拟议作品的创新和意义是由小说驱动的 免疫调节策略将提高我们对抗体介导的免疫反应的理解， 这将指导通过与CPRI Cobre的协调，继续努力开发新型免疫疗法， 减少患者CVD的燃烧。