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

基本信息

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
项目类别：
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

项目摘要

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进了对抗体介导的抗体介导的研究心血管疾病 (CVD) 的详细特征、表位特异性、抗体亚类和受体的参与将增强对CVD和治疗指南的理解患者体内 IgG 抗体诱导的一个靶标是载脂蛋白 A-I (ApoA-I)，它是 IgG 的主要蛋白质。尽管已在小鼠和人类受试者中鉴定出抗 ApoA-I 抗体，此外，这些抗体的作用尚未阐明。此外，抗体结合的免疫影响。免疫复合物（ApoA-I/IgG IC）中 ApoA-I 的作用尚不清楚。长期目标是开发新型肽。以及基于小鼠机制洞察的抗体疗法，以减轻患者的心血管疾病负担。为了实现这一目标，该提案的总体目标建立在我们对人类受试者的观察基础上表征小鼠抗 ApoA-I 抗体反应的分子成分，并将其关联起来细胞相互作用、功能结果和动脉粥样硬化进展的特征。抗 ApoA-I 抗体根据抗体的不同表现出促炎和抗炎作用导致恶化或抑制的特征（即亚类、表位特异性、Fc 受体相互作用）这项研究的基本原理是了解免疫的一个组成部分。与CVD相关的反应将通过新的治疗策略促进改善患者的治疗结果。在强有力的初步数据的鼓励下，该假设将通过两个具体目标进行检验：1）阐明靶向肽表位的抗体的分子成分和功能意义 ApoA-I；和 2) 确定 ApoA-I/IgG IC 是否通过与抑制性 Fc 受体在动脉粥样硬化易感小鼠模型中使用体外测定和体内研究。目的，将通过计算机模拟、生物物理学的关联来产生结构免疫原性关系对源自 ApoA-I 的已知肽表位进行表征和免疫原性研究。与 ApoA-I 抗体反应的抗体谱和亚类组成相关。第二个目标，抗 ApoA-I 抗体的机制影响将通过表征细胞来确定在存在特定抗 ApoA-I 谱的情况下极化并在动脉粥样硬化易感性中诱导抗体谱所提出的工作的创新性和意义是由新颖性驱动的。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，减轻患者CVD负担。