The Gene Regulatory Network Identified For Intervertebral Disc Degeneration Associated With Multiple Risk Factors And The Dynamics Of P53-Mdm2 Enrichment Signaling Pathway Mediated By MiRNA

Intervertebral Disc Degeneration(IDD)and associated inflammation often lead to low back pain,which is one of the leading causes of disability worldwide.Current treatments(physical therapy,disc replacement,etc.)can stop the progression of symptoms but cannot restore the properties of a natural disc.Studies have shown that cellular DNA damage can be caused by stimuli such as external pressure,thereby affecting the intervertebral disc cartilage.In the past,the changes of diseases were mainly focused on while the external causes were ignored.Therefore,it is of great practical significance to systematically analyze the association between IDD and risk factors,pay attention to the dynamic properties of IDD-related pathways,and provide effective suggestions for the prevention and treatment of IDD.The first chapter mainly introduces the research background,research significance and research status of IDD and p53 signaling pathway,and briefly describes the main work of this paper.The second chapter,from the perspective of systems biology,firstly analyzed the differentially expressed genes(DEGs)of IDD and its related risk factors,and revealed the molecular pathways involved in these DEGs including the p53 pathway through gene enrichment analysis.Second,the Protein-Protein Interaction(PPI)network was established using the identified common DEGs,and 10 central proteins including CCNB1,RETN,HMMR,BUB1,MPO,OIP5,HP,KIF11,BUB1 B and CDC25 A were identified through the network.Then,three key genes BUB1,BUB1 B and CCNB1 were cross-screened through the network module,and their expression may be related to the pathogenesis of IDD.Finally,three chemical drugs,dexamethasone,nicotine and resveratrol,were obtained according to gene chemical drug analysis,which may be effective drugs for IDD treatment and prevention.In the third chapter,the dynamic behavior of IDD enrichment signaling pathway p53-MDM2 under the influence of miR143 was studied.Studies have shown that miR143 is differentially expressed during IDD and it can regulate the p53 pathway.Therefore,based on the p53-MDM2 mathematical model established by predecessors,this paper considers the effect of miR143,forms a new gene regulation network,proposes a new mathematical model,and studies its dynamic properties.The results show that the dynamical properties of P53 are sensitive to some key parameters,and the time delay is also a factor that changes the dynamical state of p53.In particular,when the time delay and parameters change simultaneously,the system will produce richer dynamic behaviors,and the regulation effects on IDD are more complex and diverse.Finally,through sensitivity analysis and combined with the previous conclusions,the parameters that can most affect p53 oscillation are found out,which is the most critical parameter.The above results will help us to understand the mechanism related to IDD,so as to customize better therapeutic measures.The fourth chapter summarizes the whole paper,puts forward the innovation points and shortcomings,and prospects the future research.