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

• 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
• 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' 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

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 动脉粥样硬化性心血管疾病（ASCVD）是一种发病机制尚不清楚的炎症性疾病， 仍然是全世界发病和死亡的主要原因。免疫反应起着核心作用 CD 4 + CD 25 + Foxp 3+调节性T细胞（Tcells）在这种慢性疾病的演变中发挥关键作用， 来调节炎症我们已经显示了CD 39的表达水平，CD 39是一种免疫抑制因子， 外核苷酸酶，在人类中与特异性单核苷酸多态性遗传相关 （SNP）。尽管CD 39的选择性SNP与克罗恩病有关，但没有研究检查是否 Treg CD 39催化活性的改变，以及腺苷清除细胞外ATP的变化 ASCVD的产生、影响表现。类似地，天然存在的反义ENTPD 1-AS 1已经被克隆。 显示降低克罗恩病患者Tyndrome中的CD 39表达。用特异性自身抗体抑制ENTPD 1-AS 1 递送FANA-CD 39-AS寡核苷酸显示增加CD 39表达， 提供调节Treg表型的治疗选择。我们的总体实验目标是阐明 ASCVD中Treg CD 39表达遗传调控影响。核心假设是基因突变 导致Treg CD 39活性降低和嘌呤能反应改变， 充分缓解炎症。我们将通过进行功能基因组实验来验证这一假设， 除了使用新的小鼠实验模型系统，并开展临床研究，检查分离的 细胞和患者生物样本。该提案包括两个目标。在SA 1，我们的调查小组将确定 CD 39活性的Treg表达如何在经验证的实验系统中影响动脉粥样硬化。这将是 使用CD 39 Treg特异性条件性敲低和敲除鼠模型进行， T细胞和骨髓活化反应，以及过继转移研究。 CD 39在人T细胞上的表达，并检查CD 39调节对免疫功能的影响， ASCVD临床研究中的炎症。我们组建了一个合作团队， 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 提出的目标将发展对TcB的作用的理解，特别是CD 39的表达和改变。 嘌呤能反应，在ASCVD中，这是最重要和最重要的疾病。临床实践的转化将 通过鉴定重要的生物标志物和新靶点（包括CD 39和相关途径）来促进 腺苷能信号传导，用于ASCVD的治疗干预。