Construction Of A Gene Regulatory Network For Diabetic Complications And Design Of A Combination Drug

Background:Diabetes has become one of the most important non-infectious diseases that threaten the health of the world,affected by genetic and environmental factors,the incidence of the disease is high and the mechanism is complex.Persistent hyperglycemia and long-term metabolic disorders in diabetic patients may lead to complications,because blood sugar can't be effectively controlled.These complications are the main cause of death and disability in diabetic patients,having become a great threat to health.The main problems in the prevention and treatment of diabetic complications are as follows:The incidence rate of diabetic complications can be reduced by strict control of blood glucose by drugs,but the blood glucose standard rate in diabetic patients is low;only controling of blood sugar is difficult to reduce the risk of complications of type 2 diabetes.The combination of drugs can interfere with the occurrence and development of the disease in multiple targets and multiple ways.Traditional experimental method is difficult to select effective drug combinations from a large number of drugs quickly and efficiently,and the defect will be avoided by computer prediction.This article will use entity Grammar Systems to design the drug combination of the prevention and control of diabetic complications based on the gene regulation network.Designing drugs by regulating the level of gene expression provide a new way of thinking for the study of the key targets and drug design of the disease.Objective:The purpose of this paper is to propose a method to construct a gene regulatory network based on the gene regulation process of the organism.To construct a diabetic complication related gene regulation network and analyze the key gene of the network.The qualitative simulation method by the entity grammar system conjectured the drug affected genes and designed the effective drug combination for diabetic complications.Methods and results:(1)In view of the regulation process of genes in organisms,we have fused interactions between proteins,interactions between transcription factors and genes,interactions between miRNAs and genes,interactions between transcription factors and miRNAs,puting forward the method of constructing gene regulatory network by entity grammar system.In addition,the reliability of the method is proved by the experimental literature.(2)Using the data of diabetes complications related gene expression data,we got the differential genes of DN,DR and diabetes HF and the expression state of different genes in the disease state,and constructed the gene regulatory network of DN,DR and diabetes HF respectively.(3)Identification of key genes by gene regulatory relationships in the gene regulatory network,The key genes of DN are BMP2,VEGFA,F3,EGR2,CDS1 and PLCEI;The key genes of DR are MMP9,GNGT1,CDH1 GUCA1B,PITX2 and PPP1R1B HF;The key genes of diabetic HF are HSPA2,NRG1 and PLCE1.(4)Entity grammar system was utilized to predict the way of drug regulation of genes,the bipartite graph and greedy algorithm were used to design the smallest drug combination,and finally calculated the score of drug combinations.And the minimum drug combinations for the treatment of DN are:Palbociclib + Leuprolide + Fulvestrant.Ribociclib + Leuprolide + Fulvestrant?Abemaciclib+ Leuprolide+ Fulvestrant;the minimum drug combinations for DR are:inocycline +Flunisolide + Adapalene?Minocycline + Flunisolide + Alitretinoin?Minocycline +Flunisolide + Tazarotene;the minimum drug combination therapy of diabetes HF:Hyaluronidase + Phenylbutazone + Bosutinib.These drugs or combinations have not yet been reported about the treatment of the corresponding diabetes complications,but some drugs show the potential curative effect of hypoglycemic or other complications.The combination of drugs will produce”1+1>2" or even other new effects.