Recognition of O-GlcNAc Modified Proteins Using Site-Specific Antibodies

使用位点特异性抗体识别 O-GlcNAc 修饰蛋白

• 批准号: 10697563
• 负责人: Marla Popov
• 金额: $ 27.58万
• 依托单位: GLYCOSCIENTIFIC, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697563
• 关键词: Affinity; Age; Antibodies; Area; Arteries; Autoantigens; Binding; Biological Assay; Calmodulin; Cardiopulmonary; Cell Proliferation; Cessation of life; Characteristics; Clinical; Deterioration; Development; Diagnosis; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Enzymes; Epitopes; Exhibits; Female; Future; Glucosamine; Glucose; Goals; Health; Human; Hypertension; Immune system; Immunoprecipitation; Insulin Resistance; Lung; Metabolic; Methodology; Methods; Modification; Molecular Target; Monitor; Monoclonal Antibodies; Morphology; NOS3 gene; Nature; Nitric Oxide; O-GlcNAc transferase; Pathologic; Pathway interactions; Patients; Peptides; Phase; Phenotype; Phosphorylation; Phosphorylation Site; Post-Translational Protein Processing; Production; Protein-Carbohydrate Interaction; Proteins; Pulmonary Vascular Resistance; Pulmonary artery structure; Reagent; Recombinant Proteins; Regulation; Reporting; Research; Research Personnel; Role; Serine; Site; Specificity; Stimulus; Syndrome; System; Therapeutic; Threonine; Vascular Diseases; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Western Blotting; Work; endothelial dysfunction; glucose metabolism; glycosylation; human model; improved; in vitro Model; male; mutant; novel; novel therapeutic intervention; polyclonal antibody; premature; protein purification; pulmonary arterial hypertension; pulmonary arterial pressure; pulmonary artery endothelial cell; pulmonary vascular disorder; response; right ventricular failure; skills; targeted treatment; time interval; tool; vaccination strategy; vascular endothelial dysfunction; vasoconstriction

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery) for no apparent reason. PAH is a disease of pulmonary vascular endothelial dysfunction with nitric oxide (NO) deficiency and dysregulated glucose metabolism/utilization. It is a heterogeneous disorder likely to be comprised of overlapping syndromes with varying origins and pathobiologies that presents with many phenotypes. The idiopathic form of pulmonary arterial hypertension (IPAH) is progressive and results in the deterioration of cardiopulmonary function and premature death. The mean age at diagnosis of IPAH is 50 years with a higher female to male ratio. Presently, PAH is considered a vasculopathy, and metabolic dysregulation has emerged as a major area of research in the pathobiology of the disease. These metabolic changes results in structural and morphological changes within the lung vasculature and cause increased pulmonary artery pressure and pulmonary vascular resistance, which lead to right ventricular failure. Our lab and others have shown that IPAH patients exhibit altered levels of NO, O-GlcNAc, glucose metabolism, and insulin resistance. The nature of the primary abnormalities that trigger and perpetuate these characteristics remains unclear. Currently, all therapies in PAH target vasodilators and vasoconstrictors pathways (e.g. NO deficiency). The future of IPAH therapies depend on our ability to identify the new molecular targets within these pathways. However, the tools available to understand the role of glycosylation in human health and disease are lacking. In particular, highly specific antibodies that can recognize peptide specific sequences modified by O-GlcNAc is needed to help us better understand the disease pathobiology and improve treatment of pathologic phenotypes in IPAH. Here we propose to create the first antibodies to allow the study researchers to investigate the role of O-GlcNAc in PAH. We anticipate that these antibodies will help shed light on PAH disease mechanism(s), and potentially offer new therapeutic approaches.

肺动脉高压（PAH）是一种进行性疾病，其特征在于高血压， 血压（高血压）在肺动脉（肺动脉）的动脉没有明显的 原因的PAH是一种一氧化氮（NO）参与的肺血管内皮功能障碍性疾病 缺乏和葡萄糖代谢/利用失调。这是一种异质性疾病， 由具有不同起源和病理生物学的重叠综合征组成， 有很多表型特发性肺动脉高压（IPAH）是 进行性并导致心肺功能恶化和过早死亡。 诊断IPAH的平均年龄为50岁，女性与男性的比例较高。目前， PAH被认为是一种血管病变，代谢失调已成为一个主要领域 疾病的病理生物学研究。这些代谢变化导致结构性 和肺血管系统内的形态学变化， 压力和肺血管阻力，导致右心室衰竭。我们的实验室和 其他人已经表明IPAH患者表现出NO、O-GlcNAc、葡萄糖 代谢和胰岛素抵抗。触发和治疗的主要异常的性质 使这些特征永久化仍然不清楚。目前，PAH的所有治疗均以 血管扩张剂和血管收缩剂途径（例如NO缺乏）。IPAH疗法的未来 取决于我们在这些途径中识别新分子靶点的能力。但 缺乏可用于理解糖基化在人类健康和疾病中的作用的工具。 特别地，可以识别修饰的肽特异性序列的高度特异性抗体， 通过O-GlcNAc来帮助我们更好地了解疾病的病理生物学， IPAH中病理表型的治疗。在这里，我们建议创建第一个抗体， 允许研究人员研究O-GlcNAc在PAH中的作用。我们预计， 抗体将有助于阐明PAH疾病机制，并可能提供新的 治疗方法。