Influence of T cell genotype/phenotype in atherosclerotic cardiovascular disease

T细胞基因型/表型对动脉粥样硬化性心血管疾病的影响

基本信息

批准号：
10754115
负责人：
Richard J Gumina
金额：
$ 74.17万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10754115
关键词：
Acute Adenosine Adoptive Transfer Agonist Antisense Oligonucleotides Area Atherogenic Diet Atherosclerosis Biological Biological Markers Biological Models Biology Biometry Blood Vessels Bone Marrow Cells Cell Compartmentation Cell Separation Cell physiology Cells Chronic Chronic Disease Clinical Clinical Research Coronary Arteriosclerosis Crohn&apos s disease DNA Sequence Alteration Data Disease Endothelial Cells Evolution Exhibits Experimental Models FOXP3 gene Failure Functional disorder Generations Genes Genetic Genetic Determinism Genotype Goals Homeostasis Human IL2RA gene Immune Immune response Immunity Immunology Inflammation Inflammatory Inflammatory Response Knock-out Link Lymphoid Macrophage Mediating Molecular Morbidity - disease rate Mus Myelogenous Outcome Study Pathogenesis Pathway interactions Patients Phenotype Play Process Production Regulation Regulatory T-Lymphocyte Research Role SNP genotyping Signal Pathway Signal Transduction Single Nucleotide Polymorphism System T-Lymphocyte Testing Therapeutic Therapeutic Intervention Translations Transplantation antagonist burden of illness cell type clinical practice cohort conditional knockout driving force ecto-nucleotidase effector T cell experimental study extracellular functional genomics genetic analysis healing immune checkpoint immune function immunoregulation insight knock-down monocyte mortality mouse model new therapeutic target novel novel diagnostics novel therapeutic intervention prevent promoter response vascular inflammation

项目摘要

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) is an inflammatory disease of unclear pathogenesis that remains the leading cause of morbidity and mortality throughout the world. Immune responses play a central role in the evolution of this chronic disease, and CD4+CD25+Foxp3+ regulatory T cells (Tregs) exhibit critical functions to regulate inflammation. We have shown the level of expression of CD39, an immunosuppressive ectonucleotidase, on Tregs to be genetically associated in humans with specific single nucleotide polymorphisms (SNPs). Although select SNPs for CD39 have been linked to Crohn disease, no studies have examined whether alterations in Treg CD39 catalytic activity, and changes in extracellular ATP scavenging with adenosine generation, impact manifestations of ASCVD. Similarly, a naturally occurring antisense ENTPD1-AS1 has been shown to decrease CD39 expression in Crohn’s patient Tregs. Inhibition of ENTPD1-AS1 with a specific self- delivering FANA CD39 antisense (FANA-CD39-AS) oligonucleotide were shown to increase CD39 expression, providing a therapeutic option to modulate Treg phenotype. Our overall experimental goal is to elucidate the impact of genetic regulation of Treg CD39 expression in ASCVD. The central hypothesis is that genetic mutations resulting in decreased Treg CD39 activity and altered purinergic responses drive ASCVD due to the inability to adequately resolve inflammation. We will test this hypothesis by conducting functional genomic experiments, in addition to using novel murine experimental model systems, and develop clinical studies, examining isolated cells and patient biospecimens. The proposal consists of two Aims. In SA1, our investigative team will determine how Treg expression of CD39 activity impacts atherosclerosis in a validated experimental system. This will be done using CD39 Treg-specific conditional knock-down and knockout murine models with multiple readouts of T cell and myeloid activation responses, and adoptive transfer studies, In SA2, we will examine the regulation of CD39 expression on human Tregs and examine the impact of CD39 modulation on immune function and inflammation in clinical studies of ASCVD. We have assembled a collaborative team with clinical and experimental expertise in ASCVD, immunology, vascular biology, genetics, and biostatistics. Completion of the proposed aims will develop understanding of the role of Tregs, and specifically expression of CD39 and altered purinergic responses, in ASCVD, this most important and significant disease. Translation to clinical practice will be facilitated by identification of important biomarkers and novel targets, inclusive of CD39 and related pathways of adenosinergic signaling, for therapeutic intervention in ASCVD.

项目摘要动脉粥样硬化心血管疾病（ASCVD）是一种炎症性疾病，是一种不清楚的发病机理仍然是全世界发病率和死亡率的主要原因。免疫反应起着核心作用在这种慢性疾病的进化中，CD4+CD25+FOXP3+调节性T细胞（Tregs）暴露了关键功能调节炎症。我们已经显示了CD39的表达水平，一种免疫抑制在Treg上，在人类中与特定单核苷酸多态性相关的tregs核苷酸酶（SNP）。尽管选择CD39的选择SNP与克罗恩病有关，但尚无研究检查是否是否研究 Treg CD39催化活性的改变以及细胞外ATP清除腺苷的变化 ASCVD的产生，影响表现。同样，天然存在的反义ENTPD1-AS1已经证明可以降低克罗恩病患者的CD39表达。用特定的自我抑制ENTPD1-AS1 递送FANA CD39反义（FANA-CD39-AS）寡核苷酸可增加CD39的表达，提供一种治疗选择来调节Treg表型。我们的总体实验目标是阐明 Treg CD39表达在ASCVD中的遗传调节的影响。中心假设是遗传突变由于无法进行充分解决炎症。我们将通过进行功能基因组实验来检验该假设除了使用新型的鼠实验模型系统以及开发临床研究，检查孤立细胞和患者生物测量。该提案由两个目标组成。在SA1中，我们的调查团队将确定 CD39活性的Treg表达如何影响经过验证的实验系统中的动脉粥样硬化。这将是使用CD39 Treg特定条件敲门和淘汰鼠模型完成了多个读数 T细胞和髓样激活反应以及SA2中的自适应转移研究，我们将检查的调节 CD39对人treg的表达，并检查CD39调制对免疫功能和 ASCVD临床研究中的炎症。我们已经通过临床和 ASCVD，免疫学，血管生物学，遗传学和生物统计学方面的实验专业知识。完成拟议的目标将发展对Treg的作用，特别是CD39的作用的理解并改变了嘌呤能反应，在ASCVD中，这种最重要，最重要的疾病。转化为临床实践将通过识别重要的生物标志物和新靶标，包括CD39和相关途径用于在ASCVD中进行治疗干预的腺苷能信号。