The Construction And Phenotypic Analysis Of Protein Kinase CK2α Transgenic And Conditional Knockout Mouse Model

Aging is a process of progressive degradation of organism under the stimulation of external environment,genetic or endogenous factors at individual,tissue and cellular level.The main causes of aging include genomic instability,telomere attrition,epigenetic alterations,loss of proteostasis,deregulated nutrient sensing,mitochondrial dysfunction,stem cell exhaustion and cellular senescence,altered intercellular communication.Our understanding of the underlying mechanisms that contribute to the decline in cell and tissue functions with age has greatly advanced over the past decade.A hallmark of aging is the accumulation of dysfunctional organelles,DNA mutations,oxidized proteins and lipids which all contribute to a progressive decline in the normal physiological function of the cell and to the onset of age-related conditions.Aging is a predominant risk factor for developing cardiovascular disease.Cardiac aging is characterized by decreased cardiac function,LV hypertrophy,myocardial fibrosis and cell apoptosis,cardiac myocytes as post-mitotic cells are particularly vulnerable to age-related changes and cellular damage since they are not easily replaced,and thus have close association with aging.Studies on the functional changes of cardiac myocytes during the aging process can reflect the cardiac aging and related heart diseases.The serine/threonine protein kinase CK2 is associated with a wide variety of cellular processes,including cell growth,cell proliferation,and cell apoptosis.These cellular processes are vital for proper cell function,embryogenesis,organ homeostasis and tumorigenesis or migration.Studies have shown that CK2 knockout induces embryonic cardiac and nervous system hypoplasia,leading to embryonic death.Overexpression of CK2 can cause myocardial hypertrophy,which may be related to the excessive proliferation of myocardial cells.In recent years,CK2 is found to be an important participant in the repair of DNA damage and plays an important role in the aging process.A few endogenous protein factors that are involved in cellular senescence pathways have been found to inhibit CK2 kinase activity,such as p53,p21^WAF1.Pharmacological CK2 inhibitors used in cancer treatments cause cellular senescence,and down-regulation of CK2βactivity induces cellular senescence in Caenorhabditis elegans.Therefore,it is of great interest and importance to gain increased understanding into the mechanisms underlying CK2 induces aging and how these cellular alterations contribute to age-related pathologies.The purpose of this study is to construction of CK2αtransgenic and conditional knockout mouse model and to investigate the effect of CK2 and senescence and myocardial senescence.Results:（1）The CK2α^TG mice were successfully constructed,and phynotypes have shown including body weight loss,glucose tolerance increase and cardiac hypertrophy with age.（2）Myocardial specific conditional CK2αknockout mouse model(MYH-cre-CK2α^flox/flox)was preliminarily constructed.After Tamoxifen induction at 8 weeks of age,CK2αknockout mice were observed to have phenotypes such as cardiac dilatation,senescence related marker p21 is increased,cardiac fibrosis is increased,and cardiac function（EF and FS）is decreased.Summary:The CK2α^TG mice we construct have weight loss and increased glucose tolerance,suggesting that CK2 is closely related to the metabolism of glycolipid,while cardiac hypertrophy and cardiac dilation,cardiac fibrosis and elevated P21 phenotype after conditioning specific knockout suggest that CK2 is closely related to cardiac aging.