家族性高胆固醇血症致胸腺病理性萎缩的机制研究

Familial Hypercholesterolemia(FH)is a majar cause to Atherosclerosis（As）.According to study publications, it does not only result to local injuries, more over, it has a heavy impact on growth of immune organ and therefore leads to immunologic abnormality of the whole body. The study on this mechanism is far insufficient. In the previours study, we got some initial hints that high TC level brings impact that increase thymus atrophy, and finally takes effects to the growth of early T progenitor cells（ETPs）.Based on this: thymus is the target organ of high TC level. FH patients are the risky group for premature As. This study targets to FH patients and is baselined with growth of thymus, creates models utilited by Apoe-/- mice, and implements with methodology of immunology to observe the changes in those models, identify the possible causes of thymus atrophy and its relationship with the level of TC. Evidents to that, high TC level causes the reduce in ETPs and thymus atrophy, which indicates this mechanism of inflammation leads to As. The study will expand the knowledge of inflammation results from cholesterol from a new perspective, and takes a steps up on the system of inflammation immune on As, provides evident for the developments of new medicines for FH patients.

家族性高胆固醇血症(FH)是由多个基因突变导致的遗传代谢性疾病，既往研究多关注FH的遗传和心血管改变，忽视了高胆固醇血症对免疫系统发育的影响。申请者前期工作发现FH患儿胸腺T细胞输出功能下降，并在ApoE-/-高胆固醇血症小鼠模型中观察到胸腺萎缩，胸腺祖细胞（ETPs）比例显著下降且与血浆胆固醇水平相关。由此提出研究假说：高水平胆固醇可通过影响胸腺祖细胞发育和功能导致胸腺病理性萎缩。本研究拟以胸腺发育为切入点，结合ApoE-/-高胆固醇血症小鼠模型，在骨髓和胸腺两个发育阶段，从骨髓内造血干、祖细胞分化、向胸腺迁移和ETP自身增殖、凋亡三方面，探讨相关信号传导通路和分子机制，再以临床FH患者胸腺输出和T细胞识别功能作为验证，从免疫器官损伤的新视角拓宽对胆固醇致As炎性免疫反应的认识，为临床治疗提供新的疗效评价指标和思路。这在由生活方式改变引发的我国高胆固醇血症患病低龄化趋势下具有重要意义。

家族性高胆固醇血症（FH)是典型的动脉粥样硬化性疾病,由常染色体显性遗传，患儿血浆低密度脂蛋白胆固醇大幅增高，多伴早发动脉粥样硬化（As）。为进一步探讨高胆固醇血症致胸腺病理性老化加重免疫损伤的原因，本项目联合儿科学、免疫学、细胞生物学和病理生理学，从FH患儿外周血胸腺输出功能改变出发，以免疫细胞发育为切入点，结合ApoE-/-高胆固醇血症小鼠模型，观察模型中骨髓、胸腺淋巴前体细胞的动态变化，检测细胞增殖、凋亡、趋化和输出功能，分析并鉴别高水平胆固醇致胸腺病理性萎缩老化的可能机制及其信号通路。研究结果提示高水平胆固醇可引发胸腺输出初始T淋巴细胞的功能显著下降，ETP 的比例显著降低；且胆固醇水平与ETP 的比例数具有显著相关性。同时上述结果并未导致骨髓淋系前体细胞趋化能力的改变，提示高胆固醇血症引起的骨髓造血干祖细胞分化向髓系倾斜。本研究结果促使从免疫紊乱的角度，更全面地认识代谢性疾病的病理生理机制，最终推动代谢紊乱相关疾病的免疫治疗。本研究目前共发表论文7篇,SCI收录3篇。