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：
10002615
负责人：
Vincent Joseph Venditto
金额：
$ 38.99万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002615
关键词：
Anti-inflammatory Antibodies Antibody Response Antibody Therapy Antigen-Antibody Complex Antigens Antiinflammatory Effect Apolipoprotein A-I Arterial Fatty Streak Atherosclerosis Autoantibodies Autoantigens Autoimmune Diseases B-Cell Development B-Lymphocytes Blood Circulation Cardiovascular Diseases Cardiovascular system Characteristics Communities Data Development Disease Disease Outcome Disease Progression Epitopes Evaluation Event Exhibits Fc Receptor Formulation Foundations Future Goals High Density Lipoproteins Homeostasis Human IgG1 IgG3 Immune response Immunization Immunoglobulin G Immunologics Immunosuppression Immunosuppressive Agents Incidence Inflammatory Inflammatory Response Interleukin-10 Interleukin-12 Investigation Laboratories Measures Mediating Molecular Multi-Ethnic Study of Atherosclerosis Multivariate Analysis Mus Obesity Outcome Outcomes Research Participant Pathogenesis Patient-Focused Outcomes Patients Peptide antibodies Phenotype Plant Roots Procedures Property Prospective cohort Proteins Protocols documentation Research Risk Risk Factors Risk stratification Role Sampling Serum Specificity Stratification TLR4 gene Testing Therapeutic antibodies Time adjudicate base burden of illness cardiovascular disorder risk cardiovascular health cell mediated immune response clinical risk cohort drug development follow-up functional outcomes human subject immunoregulation improved in vivo inflammatory milieu innovation mouse model new technology new therapeutic target novel novel strategies programs prospective protocol development receptor therapeutic development treatment strategy western diet

项目摘要

PROJECT SUMMARY/ABSTRACT The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediated pathogenesis of atherosclerotic cardiovascular disease (ASCVD). One target of IgG antibody induction in ASCVD 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, their role has not been elucidated. Continued evaluation of the detailed antibody profile of ApoA-I will improve our understanding of the immune responses associated with ASCVD. The overall goal of this project is to elucidate the role of anti-ApoA-I antibodies and to characterize their molecular composition and functional impact in ASCVD. To achieve this goal, we will characterize the molecular components of the anti-ApoA-I antibody response in mice and patient serum samples and correlate these factors with cellular interactions, functional outcomes and atherosclerosis progression. The hypothesis is that anti-ApoA-I antibodies can exhibit a pro-inflammatory or anti-inflammatory effect, depending on the specific antibody characteristics (i.e., antigen engagement, subclass, epitope specificity, Fc receptor interaction), and these effects are exacerbated or suppressed in ASCVD patients. The rationale for this proposed research is that understanding one component of the humoral immune response associated with ASCVD will lead to a better understanding of the underlying mechanisms and improved patient outcomes. This hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of antibodies targeting ApoA-I in mouse models of atherosclerosis; and 2) Delineate the association between antibody profiles and ASCVD events in a large community-based prospective patient cohort. Aim 1 will employ novel immunomodulation strategies, developed in Dr. Venditto's laboratory, to achieve epitope-specific modulation of antibody responses to elucidate antibody/epitope function and role in atherosclerosis progression. In the second aim, sera from patients in the Multi-Ethnic Study of Atherosclerosis (MESA) will be evaluated for antibody profiles and correlated with patient outcomes. The approach is innovative due to the utilization of in vivo immunomodulation approaches that can alter the anti-ApoA-I IgG profiles, and our ability to achieve epitope- specific immune suppression in mice. The proposed research is significant as the outcomes of this research will improve our understanding of B cell-mediated immune responses to ApoA-I to elucidate the role of antibodies on ASCVD progression. Detailed characterizations of the antigen, epitope specificity, antibody subclass and receptor engagement will enhance understanding of ASCVD to guide therapeutic development and future efforts to improve risk stratification procedures in patients to decrease the burden of ASCVD in patients.

项目概要/摘要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动脉粥样硬化性心血管疾病（ASCVD）的发病机制。 IgG 抗体诱导的靶标之一 ASCVD患者的载脂蛋白A-I（ApoA-I）是高密度脂蛋白（HDL）的主要蛋白质。虽然反 ApoA-I 抗体已在小鼠和人类受试者中被发现，但其作用尚未阐明。继续评估 ApoA-I 的详细抗体谱将提高我们对免疫的理解与 ASCVD 相关的反应。该项目的总体目标是阐明抗 ApoA-I 的作用抗体并表征其分子组成和对 ASCVD 的功能影响。为了实现这一目标目标，我们将表征小鼠和患者抗 ApoA-I 抗体反应的分子成分血清样本并将这些因素与细胞相互作用、功能结果和动脉粥样硬化相关联进展。假设抗 ApoA-I 抗体可以表现出促炎或抗炎作用效果，取决于特定的抗体特征（即抗原结合、亚类、表位特异性、 Fc 受体相互作用），并且这些影响在 ASCVD 患者中加剧或受到抑制。理由这项拟议的研究旨在了解与体液免疫反应相关的一个组成部分 ASCVD 将有助于更好地了解其潜在机制并改善患者的治疗结果。这假设将通过两个具体目标进行检验：1）阐明分子成分和功能靶向 ApoA-I 的抗体对动脉粥样硬化小鼠模型的影响； 2) 描述关联大型社区前瞻性患者队列中的抗体谱和 ASCVD 事件之间的关系。目标1将采用 Venditto 博士实验室开发的新型免疫调节策略，以实现表位特异性调节抗体反应以阐明抗体/表位功能和在动脉粥样硬化进展中的作用。第二个目标是对动脉粥样硬化多种族研究 (MESA) 患者的血清进行评估抗体谱并与患者结果相关。该方法具有创新性，因为它利用了体内免疫调节方法可以改变抗 ApoA-I IgG 谱，以及我们获得表位的能力小鼠的特异性免疫抑制。拟议的研究具有重要意义，因为本研究的结果将提高我们对 B 细胞介导的 ApoA-I 免疫反应的理解，以阐明抗体的作用关于 ASCVD 进展。抗原、表位特异性、抗体亚类和受体参与将增强对 ASCVD 的理解，以指导治疗开发和未来的努力改进患者的风险分层程序，以减轻患者的 ASCVD 负担。