Critical roles of parkin and PINK1 in Coxsackievirus B3-induced viral myocarditis
- 주제(키워드) Myocarditis , Enterovirus , Parkin protein , PTEN-induced putative kinase , Interferon-gamma , Mitochondria
- 주제(DDC) 570
- 발행기관 아주대학교 일반대학원
- 지도교수 Sang Myun Park
- 발행년도 2024
- 학위수여년월 2024. 2
- 학위명 박사
- 학과 및 전공 일반대학원 의생명과학과
- 실제URI http://www.dcollection.net/handler/ajou/000000033793
- 본문언어 한국어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Critical roles of parkin and PINK1 in coxsackievirus B3-induced viral myocarditis Viral myocarditis is an inflammatory disease of the myocardium, often leads to cardiac dysfunction and death. PARKIN (PRKN) and PINK1, well known as Parkinson's disease-associated genes, have been reported to be involved in innate immunity and mitochondrial damage control. Therefore, we investigated the role of parkin and PINK1 in coxsackievirus B3 (CVB3)-induced viral myocarditis because the etiology of myocarditis is related to abnormal immune response to viral infection and mitochondrial damage. After viral infection, the survival was significantly lower and myocardial damage was more severe in parkin knockout (KO) and PINK1 KO mice compared to wild-type (WT) mice. Parkin KO and PINK1 KO showed defective immune cell recruitment and impaired production of antiviral cytokines such as interferon-gamma, allowing increased viral replication. In addition, parkin KO and PINK1 KO mice were more susceptible to CVB3- induced mitochondrial damage than WT mice, resulting in susceptibility to viral-induced cardiac damage. Finally, using publicly available RNA-seq data, we found that pathogenic mutants of the PRKN gene are more common in patients with dilated cardiomyopathy and myocarditis than in controls or the general population. This study will help elucidate the molecular mechanism of CVB3-induced viral myocarditis.
more목차
I. INTRODUCTION 1
A. Myocarditis and dilated cardiomyopathy (DCM) 1
B. Causes and clinical presentations of myocarditis 1
C. Coxsackievirus B3 (CVB3) 2
D. Parkinson's disease 3
E. Parkin 3
F. PINK1 4
G. Parkin and PINK1 in the defense mechanism against pathogens 5
H. Aims 5
II. MATERIALS AND METHODS 6
A. Antibodies and Reagents 6
B. Animals 6
C. Virus 7
D. Murine viral myocarditis model 7
E. Primary cardiomyocyte culture and infection with CVB3 8
F. Immunostaining 9
G. Inflammation scoring 10
H. EBD staining 10
I. RNA isolation and quantitative real-time PCR (qPCR) 10
J. Western blot analysis 13
K. IFN-γ treatment 13
L. Transmission electron microscopy (TEM) 13
M. Echocardiogram 14
N. Public RNA-seq data and variants calling 14
O. Statistical analysis 15
III. RESULTS 16
Part A. Effects of parkin and PINK1 on the progression of viral myocarditis 16
Part B. Effects of parkin and PINK1 on antiviral immunity 22
Part C. Effects of parkin and PINK1 on mitochondrial vulnerability 42
Part D. Pathogenic variants of parkin and PINK1 in patients 46
IV. DISCUSSION 54
V. CONCLUSION 62
VI. REFERENCES 63
국문요약 74
