Vitamin D binding protein (DBP) in innate immune cell response in viral myocarditis

维生素 D 结合蛋白 (DBP) 在病毒性心肌炎先天免疫细胞反应中的作用

• 批准号: 10283225
• 负责人: Katelyn Ann Bruno
• 金额: $ 23.48万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283225
• 关键词: Adult; Affect; Age; Animal Model; Autoimmune Diseases; Binding Proteins; Biological Assay; Biological Markers; Blood; C5a anaphylatoxin receptor; Cardiac; Cardiovascular Diseases; Cells; Cessation of life; Chemotaxis; Child; Chromosomes; Clinic; Clinical; Clinical Data; Code; Complement; Complement 5a; Complement Activation; Computerized Medical Record; Congestive Heart Failure; Cytometry; Diagnosis; Dilatation - action; Dilated Cardiomyopathy; Disease; Echocardiography; Estrogens; Female; Gender; Goals; Gonadal Steroid Hormones; Healthcare; Heart; Heart Transplantation; Heart failure; Hormones; ICD-9; Immune; Incidence; Individual; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Interferon Type II; Interleukin-1 beta; Left Ventricular Ejection Fraction; Measures; Mediating; Methods; Modeling; Mouse Protein; Mus; Myocardial; Myocarditis; Neutrophil Infiltration; New York; Pathway interactions; Patient Care; Patients; Plasma; Pre-Clinical Model; Proteomics; Recombinant Proteins; Recombinants; Regulatory Pathway; Research; Risk; Sampling; Serum; Severities; Severity of illness; Sex Differences; Sudden Death; Techniques; Testing; Testosterone; Therapeutic; Virus Diseases; Vitamin D-Binding Protein; Woman; biobank; cofactor; diagnostic biomarker; experimental study; high dimensionality; improved; in vivo; individualized medicine; innate immune mechanisms; innovation; insight; male; men; mouse model; neutrophil; novel; novel marker; older men; older women; pre-clinical; predictive marker; prevent; protein expression; recruit; response; response to injury; sex; symptom treatment; targeted treatment; tissue injury; viral myocarditis; young adult; young man

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.

项目摘要 病毒感染引起的心肌炎是年轻人猝死的主要原因， 扩张型心肌病（DCM）和心脏移植的需要。临床上需要更好地 了解心肌炎的先天免疫反应机制，以改善 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。 男性心血管疾病（包括心肌炎/扩张型心肌病）的发病率和严重程度高于女性。 在一项蛋白质组学研究中，我们发现血清维生素D结合蛋白（DBP）和补体成分是 与女性相比，心肌炎男性中的表达上调，这表明DBP和DBP的性别差异 补体可增加男性心脏炎症。DBP在天然免疫中的作用及其机制 细胞在心肌炎中的作用以前没有研究过。在高度转化的临床前动物模型中， 发现DBP缺乏的雄性小鼠的炎症和补体成分显著减少 包括C3和C5/C5 a与野生型对照相比，表明DBP增加了男性心肌炎 小鼠本研究旨在探讨心肌炎患者血浆DBP水平的性别差异是否与 心力衰竭的测量，如纽约心脏协会分级，心力衰竭生物标志物，性激素 和/或补体成分。我们将进一步确定DBP增加先天性高血压的机制。 使用DBP缺陷小鼠，C5 a受体拮抗剂，导致心脏炎症增加的免疫系统 和C5 a重组蛋白。我们还将研究性激素对DBP的影响， 病毒性心肌炎期间的补体成分，通过观察DBP、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， 提供了循环DBP作为一种新的生物标志物的机制理解，该生物标志物可用于预测 心肌炎导致心力衰竭的风险，并确定靶向DBP的治疗是否可以降低先天性心脏病的风险。 免疫细胞募集和/或预防心肌炎和猝死。