基于野生型来源1号染色体替换系的自发性血脂模型的建立与机制研究

High blood lipid is a serious chronic disease affecting human health. the classic genetic mutations animal models or high fat diet-induced models showing poor phenotypic stability, can hardly mimic the mechanism of human lipid disease (caused by multiple genes and environmental factors). Therefore, the basic research and drug discovery of high blood lipid need the development of new animal models..Our group owns the exclusive 25 chromosome 1 substitution lines from Chinese wild mice. Whole-genome sequencing confirmed that these strains' genome diversity significantly different common inbred mice, suggesting that they may be associated with phenotypic diversity. Preliminary data shows that under non-inducing conditions, some of the strains showed significant lipid metabolism disorders. Hepatic gene expression data also suggest that the pathway of lipid metabolism-related gene expression of these new strains different from common inbred mice..This research will select these strains with various lipid index (TC, and TG, and HDL-C, and LDL-C), and carry out detailed phenotype analysis and research. We will get the standardization pathology, biochemical data and liver expression data during disease developing process, while using clinical drug screening and the genomic targeting, to validate the disease mechanism. Eventually we will established 2-3 new lipid disorder models based on multi-gene interaction, with genetic and phenotypic stability.

高血脂是严重影响人类健康的慢性疾病。经典的遗传突变诱导或高脂饲料诱导的动物模型形成机制与人类发病机制（多基因和多环境因素）差异较大，表型稳定性也较差。因此，高血脂的基础研究和药物研发亟需新的动物模型。.课题组拥有国际上独有的25个野生小鼠来源的1号染色体的替换系小鼠品系，全基因组测序证实这些品系基因组多样性明显有别于普通近交系小鼠，提示其可能伴随表型多样性。初步鉴定表明在非诱导条件下，部分品系表现出明显血脂代谢紊乱，肝脏基因表达谱数据也提示血脂代谢相关的通路基因表达和普通近交系小鼠不同。.本研究将选取这些血脂代谢异常的品系，针对各类血脂指标（TC、TG、HDL-C、LDL-C）开展细致表型分析和研究，获得这些模型在疾病发生过程中的标准化病理、生化和肝脏表达谱数据，同时利用临床药物筛选及基因组编辑等手段验证可能的发病机理，最终建立2-3个全新的、基于多基因相互作用和可稳定遗传的高血脂模型。

高血脂是严重影响人类健康的慢性疾病。经典的遗传突变诱导或高脂饲料诱导的动物模型形成机制与人类发病机制（多基因和多环境因素）差异较大，表型稳定性也较差。因此，高血脂的基础研究和药物研发亟需新的动物模型。全基因组测序证实野生小鼠来源的1号染色体的替换系小鼠品系基因组多样性明显有别于普通近交系小鼠，提示其可能伴随表型多样性。.为了建立起更接近于人类血脂异常疾病的模型，本项目首先对已经稳定遗传的野生1号染色体替换系小鼠进行血脂表型的初步筛选，从中找出了异常模型来进行进一步表型的确认和发病过程的详细测定，并对获得的血脂异常模型进行分类。根据血脂代谢异常的品系的各类血脂指标（TC、TG、HDL-C、LDL-C），我们可以把各品系进行分类，B6/JGpt-Chr1JD(jhxiao)/Gpt♂、B6/JGpt-Chr1SJ(jhxiao)/Gpt♂和B6/JGpt-Chr1SJ(jhxiao)/Gpt♀、B6/JGpt-Chr1CM(jhxiao)/Gpt♂、B6/JGpt-Chr1BLD(jhxiao)/Gpt♂、B6/JGpt-Chr12-ZZ2(jhxiao)/Gpt♂归类为TC升高的高血脂，把B6/JGpt-Chr1LY(jhxiao)/Gpt♀归类为TG升高的高血脂，B6/JGpt-Chr1HZ(jhxiao)/Gpt♂和B6/JGpt-Chr1HZ(jhxiao)/Gpt♀归类为TG、TC均升高混合型高血脂。.为了进一步利用这些模型对血脂异常这一基于多基因疾病的发病机理机制进行挖掘，对获得的血脂异常模型进行分子特征数据的收集和分析，本项目收集了不同品系小鼠新鲜肝脏组织样本，基于RNA-seq技术获得基因表达谱。通过对差异表达的基因进行功能注释(Gene Ontology, GO)和KEGG Pathway功能分析确认差异表达基因与哪些生物学功能显著相关，并且对于其中与脂代谢相关的关键性蛋白进行了进一步分析。最终确定了B6/JGpt-Chr1BLD(jhxiao)/Gpt的雄鼠以及B6/JGpt-Chr1HZ(jhxiao)/Gpt的雄鼠和雌鼠可以作为全新的、基于多基因相互作用和可稳定遗传的高血脂模型。这一研究将为了解人类血脂异常发病机理提供有力的证据，为新药研究筛选出新的靶点， 并为临床精确诊断和精准用药提供基础。