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

基本信息

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
项目类别：
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

项目摘要

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突然死亡的主要原因，可以发展为扩张的心肌病（DCM），需要心脏移植。有临床需要更好了解心肌炎潜在的先天免疫反应的机制，以改善诊断并防止猝死。大多数自身免疫性和心血管疾病都存在性别差异。男性的心血管疾病（包括心肌炎/DCM）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，心肌炎男性的上调，表明DBP和补体可能会增加男性心脏炎症。 DBP先天免疫的活性和机制心肌炎的细胞先前尚未研究。在高度翻译的临床前动物模型中发现缺乏DBP的雄性小鼠显着减少炎症和补体成分与野生型对照相比，包括C3和C5/C5A，表明DBP会增加男性心肌炎老鼠。这项研究检查了心肌炎患者血浆DBP水平的性别差异是否相关诸如纽约心脏协会课程，心力衰竭生物标志物，性激素等心力衰竭的度量和/或补充组件。我们将进一步定义DBP先天的机制免疫系统，导致使用DBP缺乏小鼠C5A受体拮抗剂增加心脏炎症和C5A重组蛋白。我们还将研究性激素对DBP和通过查看DBP，补充和性激素水平。该研究的成功完成将显着影响提供对循环DBP作为一种新型生物标志物的机械理解，可用于预测心肌炎患心力衰竭的风险，并确定针对DBP的疗法是否可以减少先天性免疫细胞募集和/或预防心肌炎和猝死。