Vitamin D Binding Protein (DBP) in Innate Immune Cell Response in Viral Myocarditis

病毒性心肌炎先天免疫细胞反应中的维生素 D 结合蛋白 (DBP)

• 批准号: 10744357
• 负责人: Katelyn Ann Bruno
• 金额: $ 17.67万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-22 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744357
• 关键词: Vitamin; Binding; Protein; DBP; Innate

PROJECT SUMMARY Myocarditis caused by viral infections is a leading cause of sudden death in young adults and can progress to dilated cardiomyopathy (DCM) and the need for a heart transplant. There is a clinical need to better understand the mechanisms of the innate immune response underlying myocarditis in order to improve diagnosis and prevent sudden death. Sex differences exist for most autoimmune and cardiovascular diseases. Men have a higher incidence and severity of cardiovascular diseases including myocarditis/DCM than women. In a proteomics study we found that serum vitamin D binding protein (DBP) and complement components were upregulated in men with myocarditis compared to women, suggesting that sex differences in both DBP and complement may increase cardiac inflammation in men. The activity and mechanism of DBP in innate immune cells in myocarditis has not been previously investigated. In a highly translational preclinical animal model we found that male mice deficient in DBP have significantly reduced inflammation and complement components including C3 and C5/C5a compared to wild type controls indicating that DBP increases myocarditis in male mice. This study examines whether sex differences in plasma DBP levels in patients with myocarditis correlate to measures of heart failure like New York Heart Association Class, heart failure biomarkers, sex hormones and/or complement components. We will further define the mechanisms whereby DBP increases the innate immune system leading to increased cardiac inflammation using DBP deficient mice, C5a receptor antagonist and C5a recombinant protein. We will additionally examine the effect of sex hormones on DBP and complement components during viral myocarditis by looking at correlations between DBP, complement and sex hormone levels. The successful completion of the study will significantly impact the field of myocarditis by providing a mechanistic understanding of circulating DBP as a novel biomarker that may be used to predict the risk of heart failure from myocarditis and determine whether therapies targeting DBP could reduce innate immune cell recruitment and/or prevent myocarditis and sudden death.

项目总结 由病毒感染引起的心肌炎是导致年轻人猝死的主要原因，并可进展为 扩张型心肌病(DCM)和心脏移植的需要。临床上有必要更好地 了解心肌炎的先天免疫反应机制，以改善心肌炎 诊断和预防猝死。大多数自身免疫性疾病和心血管疾病存在性别差异。 男性的心肌炎/扩张性心肌炎等心血管疾病的发病率和严重程度均高于女性。 在蛋白质组学研究中，我们发现血清维生素D结合蛋白(DBP)和补体成分 与女性相比，男性心肌炎患者的DBP和DBP的性别差异 补体可能会增加男性的心脏炎症。DBP在先天免疫中的作用及其机制 心肌炎中的细胞以前还没有被研究过。在高度翻译的临床前动物模型中，我们 发现缺乏DBP的雄性小鼠显著减少了炎症和补体成分 包括C3和C5/C5a与野生型对照相比，表明DBP增加了男性心肌炎 老鼠。这项研究调查了心肌炎患者血浆DBP水平的性别差异是否相关 到衡量心力衰竭的指标，如纽约心脏协会分类，心力衰竭生物标志物，性激素 和/或补充组件。我们将进一步定义DBP增加先天的 使用C5a受体拮抗剂DBP缺陷小鼠的免疫系统导致心脏炎症增加 和C5a重组蛋白。此外，我们还将检验性激素对舒张压和 病毒性心肌炎时补体成分与舒张压、补体和 性激素水平。这项研究的成功完成将对心肌炎领域产生重大影响 提供了对循环DBP作为一种新的生物标志物的机械理解，该生物标志物可用于预测 心肌炎导致心力衰竭的风险，并确定针对DBP的治疗是否可以降低先天 免疫细胞募集和/或预防心肌炎和猝死。