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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.

项目总结