EN
心血管代谢相关疾病研究

随着人类对感染性疾病的有效控制及人群生活方式的改变,脂肪肝与糖尿病、血脂异常、动脉粥样硬化、高血压等代谢性相关疾病的发病率呈逐年上升趋势,并成为导致人群死亡的最主要原因。肝脏是人体最重要的代谢器官之一,全球超过20亿人患有肝病,非酒精性脂肪肝病(nonalcoholic fatty liver  disease, NAFLD)的平均患病率接近30%,临床上约10%的单纯性脂肪肝会进展至脂肪性肝炎(nonalcoholic  steatohepatitis,NASH)阶段,其中将有20%-40%可发展成为肝纤维化和肝硬化(Hepatic Cirrhosis,HC),最终导致肝癌(hepatocellular carcinoma, HCC)。另有研究表明NAFLD不仅和肥胖、糖尿病及胰岛素抵抗密切相关,NAFLD的严重程度还与心血管疾病的发生风险间也存在着密切的联系。但迄今为止,针对NAFLD/NASH、动脉粥样硬化等代谢性相关疾病的干预和治疗方法非常缺乏。因此,探索代谢相关性疾病的发病机制,寻找新的预防和治疗靶点,对于其预防、诊断和治疗具有重要意义。

针对代谢相关性疾病基础研究和临床诊疗方面的重大需求,武汉大学模式动物研究所逐步形成了以医学分子生物学专业背景为主体,覆盖理学、工学和医学三大学科门类,分子生物学、细胞生物学、病理生理学、生物医学工程、肝脏学、心血管、代谢、肿瘤、临床医学等十余个学科的多学科交叉互补创新团队。团队以武汉大学动物实验中心为依托,以肝脏和心血管代谢相关重大疾病为导向,在基础研究、转化研究和临床治疗三个层次上,系统性地开展代谢相关性疾病的研究工作。

相关论文(主要论文链接)

【我们团队发表的综述】

  1. Xu  M, Liu PP, Li H. Innate Immune Signaling and Its Role in Metabolic and  Cardiovascular Diseases. Physiol Rev 2019; 99:893-948.    
  2. Cai  J, Xu M, Zhang X, Li H. Innate Immune Signaling in Nonalcoholic Fatty Liver  Disease and Cardiovascular Diseases. Annu Rev Pathol 2019;14:153-184.    
  3. Bai L, Li H. Innate immune regulatory networks in hepatic lipid metabolism. J Mol Med (Berl). 2019.    
  4. Cai J, Zhang XJ, Li H. Progress and challenges in the prevention and control of nonalcoholic fatty liver disease. Med Res Rev 2019; 39(1):328-348.    
  5. Cai J, Zhang XJ, Li H. The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis. Hepatology. 2019.    
  6. Yu Y, Cai J, She Z, Li H. Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases. Adv Sci (Weinh) 2018; 12; 6(4):1801585.    
  7. Cai J, Zhang XJ, Li H. Role of Innate Immune Signaling in Non-Alcoholic Fatty Liver Disease. Trends Endocrinol Metab 2018; 29(10):712-722.    
  8. Zhang Y, Huang Z, Li H. Insights into innate immune signalling in controlling cardiac remodelling. Cardiovasc Res 2017; 113(13):1538-1550.    
  9. Zhang Y, Li H. Reprogramming Interferon Regulatory Factor Signaling in Cardiometabolic Diseases. Physiology (Bethesda) 2017; 32(3):210-223.    
  10. Zhang Y, Zhang XJ, Wang PX, Zhang P, Li H. Reprogramming Innate Immune Signaling in Cardiometabolic Disease. Hypertension 2017; 69(5):747-760.    
  11. Wang W, Zhang Y, Yang L, Li H. The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes? Cancer Lett 2017; 28; 387:46-60.    
  12. Zhang Y, Zhang XJ, Li H. Targeting Interferon Regulatory Factor for Cardiometabolic Diseases: Opportunities and Challenges. Curr Drug Targets 2017; 18(15):1754-1778.    
  13. Wang P, Zhang X, Li H. Liver capsule: IRFs in hepatocytes: Pathophysiology. Hepatology 2016; 63:1706-1706.    
  14. Zhang XJ, Jiang DS, Li H. The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases. Br J Pharmacol 2015; 172(23):5457-76.    
  15. Zhang XJ, Zhang P, Li H. Interferon regulatory factor signalings in cardiometabolic diseases. Hypertension 2015; 66(2):222-47.    
  16. Zhao GN, Jiang DS, Li H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. Biochim Biophys Acta 2015; 1852(2):365-78.    
  17. Zhang X, Wang P, Zhang P, Li H. Reply to: “Interferon regulatory factor 9 plays a dual function in health and disease”. J Hepatol 2015; 62:1447-1448.    

1.非酒精性脂肪肝病

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,  NAFLD)是一组与全身性代谢紊乱密切相关的代谢应激性肝脏疾病,疾病谱包括非酒精性单纯性脂肪肝(nonalcoholic  simple fatty liver,  NAFL)和非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH),疾病进展有发生肝硬化甚至肝癌的高风险。近年来,NAFLD的发病率不断提高,根据全球流行病调查结果显示,NAFLD是世界范围内慢性肝病的首要病种,在成年人中的发病率高达20%~40%,而肥胖人群中的发病率达到75%,严重危害公众健康。目前临床上尚无有效治疗NASH的药物, 原因主要在于NASH发病存在很大的异质性, 且决定NASH进展的关键机制尚不明确。因此,深入探索NASH的发病机制,找到决定NASH进展的关键靶点,是一项重要且急迫的科学任务。本团队围绕NASH的调控靶分子进行大量研究工作,系统探索了天然免疫网络调控分子在肝脏代谢紊乱中的作用。系列研究成果发表在国际顶级杂志自然·医学(Nat Med)、肝脏病学(Hepatology)、肝脏病学杂志(Journal of Hepatology)等国际一流学术期刊。

相关论文(主要论文链接)

  1. Tong J, Han CJ, Zhang JZ, He WZ, Zhao GJ, Cheng X, Zhang L, Deng KQ, Liu Y, Fan HF, Tian S, Cai J, Huang Z, She ZG, Zhang P, Li H. Hepatic IRF6 alleviates liver steatosis and metabolic disorder by transcriptionally suppressing PPARγ. Hepatology 2019.    
  2. Zhang P, Wang PX, Zhao LP, Zhang X, Ji YX, Zhang XJ, Fang C, Lu YX, Yang X, Gao MM, Zhang Y, Tian S, Zhu XY, Gong J, Ma XL, Li F, Wang Z, Huang Z, She ZG, Li H. The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nat Med 2018; 24:84-94.    
  3. Ji YX, Huang Z, Yang X, Wang X, Zhao LP, Wang PX, Zhang XJ, Alves-Bezerra M, Cai L, Zhang P, Lu YX, Bai L, Gao MM, Zhao H, Tian S, Wang Y, Huang ZX, Zhu XY, Zhang Y, Gong J, She ZG, Li F, Cohen DE, Li H. The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis. Nat Med 2018; 24:213-223.    
  4. Wang PX, Ji YX, Zhang XJ, Zhao LP, Yan ZZ, Zhang P, Shen LJ, Yang X, Fang J, Tian S, Zhu XY, Gong J, Zhang X, Wei QF, Wang Y, Li J, Wan L, Xie Q, She ZG, Wang Z, Huang Z, Li H. Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat Med 2017; 23:439-449.    
  5. Zhao GN, Zhang P, Gong J, Zhang XJ, Wang PX, Yin M, Jiang Z, Shen LJ, Ji YX, Tong J, Wang Y, Wei QF, Wang Y, Zhu XY, Zhang X, Fang J, Xie Q, She ZG, Wang Z, Huang Z, Li H. Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med 2017; 23:742-752.    
  6. Yan FJ, Zhang XJ, Wang WX, Ji YX, Wang PX, Yang Y, Gong J, Shen LJ, Zhu XY, Huang Z, Li H. The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis. Hepatology 2017; 65:1492-1511.    
  7. Xie L, Wang P, Zhang P, Zhang X, Zhao G, Wang A, Guo J, Zhu X, Zhang Q, Li H. DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity. J Hepatol 2016; 65:113-124.    
  8. Gao L, Wang P, Zhang Y, Yu C, Ji Y, Wang X, Zhang P, Jiang X, Jin H, Huang Z, Zhang Z, Li H. Tumor necrosis factor receptor-associated factor 5 (Traf5) acts as an essential negative regulator of hepatic steatosis. J Hepatol 2016; 65:125-136.    
  9. Wang P, Zhang X, Luo P, Jiang X, Zhang P, Guo J, Zhao G, Zhu X, Zhang Y, Yang S, Li H. Hepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling. Nat Commun 2016; 7:10592.    
  10. Xiang M, Wang P, Wang A, Zhang X, Zhang Y, Zhang P, Mei F, Chen M, Li H. Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis. J Hepatol 2016; 64:1365-1377.    
  11. Zhu LH, Wang A, Luo P, Wang X, Jiang DS, Deng W, Zhang X, Wang T, Liu Y, Gao L, Zhang S, Zhang X, Zhang J, Li H. Mindin/Spondin 2 inhibits hepatic steatosis, insulin resistance, and obesity via  interaction with peroxisome proliferator-activated receptor alpha in mice. J Hepatol 2014; 60:1046-54.    
  12. Wang XA, Zhang R, She ZG, Zhang XF, Jiang DS, Wang T, Gao L, Deng W, Zhang SM, Zhu LH, Guo S, Chen K, Zhang XD, Liu DP, Li H. Interferon regulatory factor 3 constrains IKKbeta/NF-kappaB signaling to alleviate hepatic steatosis and insulin resistance. Hepatology 2014; 59:870-85.    
  13. Wang XA, Zhang R, Jiang D, Deng W, Zhang S, Deng S, Zhong J, Wang T, Zhu LH, Yang L, Hong S, Guo S, Chen K, Zhang XF, She Z, Chen Y, Yang Q, Zhang XD, Li H. Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice. Hepatology 2013; 58:603-16.    

2.肝脏缺血再灌注

如无有效控制,非酒精性脂肪性肝病会逐渐发展为肝脏终末期病变。目前肝脏切除和移植是治疗终末期肝病的主要手段,但缺血再灌注是此类手术中不可避免的过程,表现为缺血器官或组织在血流重建后,不仅不能恢复正常功能,反而使组织结构破坏加重和器官功能的进一步恶化。目前已知,缺血再灌注可导致心、脑、肝、肺、肾、肠等多器官功能损伤,其中以肝脏缺血再灌注损伤最为普遍和严重,可广泛引发肝脏功能失常、组织排异反应、肝脏移植失败,最终引起肝脏功能衰竭甚至死亡,并可发生远隔组织或器官功能失常的级联反应。据统计,由缺血再灌注损伤引起的早期肝脏移植后器官功能衰竭比例达到10%,而由其导致的急慢性组织排异现象更为常见,极大限制了肝脏切除术的适应症和边缘性肝脏供体在肝脏移植中的应用。肝脏缺血再灌注方面,本研究团队通过转录组学、蛋白组学、代谢组学等多组学联合分析手段,首次提出缺血过程中脂质代谢通路的重编程是肝脏缺血再灌注损伤的根本发病原因的新概念,尤其是以 ALOX12 显著升高为特征的花生四烯酸代谢通路的紊乱变化最为显著。值得注意的是,本团队基于前期系列研究,发现小分子化合物ML355是治疗肝脏缺血再灌注损伤的先导化合物,并在非人灵长类动物恒河猴模型中得到有效证实。此外,本研究团队在肝脏缺血再灌注领域深入探讨了系列天然免疫核心调控网络分子对肝损伤的影响及其机制。系列研究成果发表在国际顶级杂志自然·医学(Nat Med)、肝脏病学(Hepatology)、肝脏病学杂志(Journal of Hepatology)等国际一流学术期刊。

相关论文(主要论文链接)

  1. Zhang XJ, Cheng X, Yan ZZ, Fang J, Wang X, Wang W, Liu ZY, Shen LJ, Zhang P, Wang PX, Liao R, Ji YX, Wang JY, Tian S, Zhu XY, Zhang Y, Tian RF, Wang L, Ma XL, Huang Z, She ZG, Li H. An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury. Nat Med 2018; 24:73-83.    
  2. Qin JJ, Mao W, Wang X, Sun P, Cheng D, Tian S, Zhu XY, Yang L, Huang Z, Li H. Caspase recruitment domain 6 protects against hepatic ischemia/reperfusion injury by suppressing ASK1. J Hepatol. 2018; 69(5):1110-1122.    
  3. Wang X, Mao W, Fang C, Tian S, Zhu X, Yang L, Huang Z, Li H. Dusp14 protects against hepatic ischaemia-reperfusion injury via Tak1 suppression. J Hepatol 2017; 68: 118–129.    
  4. Hu J, Zhu X, Zhang X, Wang P, Zhang R, Zhang P, Zhao G, Gao L, Zhang X, Tian S, Li H. Targeting TRAF3 signaling protects against hepatic ischemia/reperfusions injury. J Hepatol 2016; 64:146-159.    
  5. Wang P, Zhang R, Huang L, Zhu L, Jiang D, Chen H, Zhang Y, Tian S, Zhang X, Zhang X, Liu D, Li H. Interferon regulatory factor 9 is a key mediator of hepatic ischemia/reperfusion injury. J Hepatol 2015; 62:111-120.    
  6. Sun P, Zhang P, Wang P, Zhu L, Du Y, Tian S, Zhu X, Li H. Mindin deficiency protects the liver against ischemia/reperfusion injury. J Hepatol 2015; 63:1198-1211.    

3.心衰及心脏重构

近年来,心血管疾病发病率持续增加,已成为严重威胁我国居民健康和社会发展的重大公共卫生问题。心力衰竭是心室充盈和(或)射血功能受损,心脏排血量不能满足机体组织代谢需要的临床综合征,是临床上各种心血管疾病的最终结局。病人一旦发生心力衰竭,就步入了一个进行性恶化的过程。美国Framingham连续40年研究显示心力衰竭5年生存率在男性为25%,女性为38%,与恶性肿瘤相当。尽管近年来心血管疾病的介入治疗以及血管紧张素转换酶抑制剂、血管紧张素受体拮抗剂及β受体阻滞剂的应用可以改善部分心力衰竭患者的预后,但心力衰竭的总生存率仍很低。寻找积极有效的干预措施遏制甚至逆转心力衰竭的进展迫在眉睫。心脏重构是一个复杂的,有众多细胞类型和信号分子参与的病理过程,是心力衰竭发生发展的必经阶段。阐明心脏重构发生发展的分子机理能为未来寻找防治心力衰竭的新靶点奠定理论基础,为临床实践提供指导方针,具有重大的科学意义和社会意义。本研究团队以心脏重构为切入点,在过去十余年里开展了大量研究,系统阐明了天然免疫信号网络在心脏重构中的动态变化和精细调控机制,并得到了国际同行的高度关注和一致认可。除此之外,本团队对某些重要分子的临床治疗转化进行了尝试。未来,我们将充分发挥本团队大动物模型的优势,结合靶向药物的筛选与开发,为临床治疗心血管代谢性疾病提供新靶标和新策略。系列研究成果发表在国际顶级杂志《自然·医学》(Nat Med)、循环(Circulation)、自然·通讯(Nature Communication)等国际一流学术期刊。

相关论文(主要论文链接)

  1. Cai J, Li H. A novel RIT1 mutation causes deterioration of Noonan syndrome-associated cardiac hypertrophy. EBioMedicine 2019; 20. pii: S2352-3964(19)30197-5.    
  2. Deng KQ, Zhao GN, Wang Z, Fang J, Jiang Z, Gong J, Yan FJ, Zhu XY, Zhang P, She ZG, Li H*. Targeting Transmembrane BAX Inhibitor Motif Containing 1 Alleviates Pathological Cardiac Hypertrophy. Circulation. 2018; 137(14):1486-1504.    
  3. Wang Z, Zhang X, Ji Y, Zhang P, Deng K, Gong J, Ren S, Wang X, Chen I, Wang H, Gao C, Yokota T, Ang YS, Li S, Cass A, Vondriska TM, Li G, Deb A, Srivastava D, Yang H, Xiao X, Li H, Wang Y. The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med 2016; 22:1131-1139.    
  4. Deng K, Wang A, Ji Y, Zhang X, Fang J, Zhang Y, Zhang P, Jiang X, Gao L, Zhu X, Zhao Y, Gao L, Yang Q, Zhu X, Wei X, Pu J, Li H. Suppressor of IKK? is an essential negative regulator of pathological cardiac hypertrophy. Nat Commun 2016; 7:11432.    
  5. Ji Y, Zhang P, Zhang X, Zhao Y, Deng K, Jiang X, Wang P, Huang Z, Li H. The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling. Nat Commun 2016; 7:11267.    
  6. Jiang DS, Wei X, Zhang XF, Liu Y, Zhang Y, Chen K, Gao L, Zhou H, Zhu XH, Liu PP, Bond LW, Ma X, Zou Y, Zhang XD, Fan GC, Li H. IRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling. Nat Commun 2014; 5:3303.    
  7. Li H, He CW, Feng JH, et al. Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. Proc Natl Acad Sci U S A. 2010;107:13818-13823    

4.动脉粥样硬化及内膜新生

心脑血管疾病在全球范围都表现出极高的发病率和致死率,而动脉粥样硬化(Atherosclerosis)是众多心脑血管疾病最常见的病理基础。动脉硬化晚期发生的血管附着斑块的破裂以及随后发生的血栓形成阻塞血液循环,是直接引起急性心肌梗死及脑梗塞等心血管事件发生,导致西方发达国家人口死亡的主要原因,并且有广泛蔓延到全球范围的趋势。近年来,血管内介入治疗技术的日益更新,各级治疗机构的不断建立、完善,各种治疗手段的不断进步以及预防控制危险因素药物的使用,虽然可以明显降低冠心病等疾病的病死率,但是相应的慢性疾病患病率的升高,以及手术过程中出现的不同程度的机械损伤引起的新生内膜的形成,导致支架术后再狭窄情况的发生,使得疗效往往不尽如人意,使得治疗费用大大增加。因此,寻找有效逆转动脉粥样硬化进程,抑制平滑肌细胞表型转化、增殖、迁移导致的血管再狭窄的机制及探究新的治疗靶点具有重要的理论和临床意义。在过去的十年时间,以干扰素调节因子(Interferon Regulator Factors)家族成员为契口,我们团队致力于阐明天然免疫相关分子对血管增生性疾病的调控作用和机制。系列研究成果发表在国际顶级杂志循环(Circulation)、循环研究(Circulation Research)等国际一流学术期刊。

相关论文(主要论文链接)

  1. Zhi H, Gong FH, Cheng WL, Zhu K, Chen L, Yao Y, Ye X, Zhu XY, Li H. Tollip Negatively Regulates Vascular Smooth Muscle Cell-Mediated Neointima Formation by Suppressing Akt-Dependent Signaling. J Am Heart Assoc 2018; 7(12). pii: e006851.    
  2. Jiang Z, Qin JJ, Zhang Y, Cheng WL, Ji YX, Gong FH, Zhu XY, Zhang Y, She ZG, Huang Z, Li H. LILRB4 deficiency aggravates the development of atherosclerosis and plaque instability by increasing the macrophage inflammatory response via NF-κB signaling. Clin Sci (Lond) 2017. pii: CS20170198.    
  3. Zhang X, Li J, Qin JJ, Cheng WL, Zhu X, Gong FH, She Z, Huang Z, Xia H, Li H. Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages. J Lipid Res 2017; 58(5):895-906.    
  4. Cheng WL, Yang Y, Zhang XJ, Guo J, Gong J, Gong FH, She ZG, Huang Z, Xia H, Li H. Dickkopf-3 Ablation Attenuates the Development of Atherosclerosis in ApoE-Deficient Mice. J Am Heart Assoc. 2017; 6(2). pii: e004690.    
  5. Chao ML, Guo J, Cheng WL, Zhu XY, She ZG, Huang Z, Ji Y, Li H. Loss of Caspase-Activated DNase Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice. J Am Heart Assoc 2016; 5(12). pii: e004362.    
  6. Cheng WL, She ZG, Qin JJ, Guo JH, Gong FH, Zhang P, Fang C, Tian S, Zhu XY, Gong J, Wang ZH, Huang Z, Li H. Interferon Regulatory Factor 4 Inhibits Neointima Formation by Engaging Kruppel-Like Factor 4 Signaling. Circulation 2017; 136:1412-1433.    
  7. Zhang SM, Zhu LH, Chen HZ, Zhang R, Zhang P, Jiang DS, Gao L, Tian S, Wang L, Zhang Y, Wang PX, Zhang XF, Zhang XD, Liu DP, Li H. Interferon regulatory factor 9 is critical for neointima formation following vascular injury. Nat Commun 2014; 5:5160.    
Copyright© 武汉大学模式动物研究所。保留所有权利。 地址:中国·武汉 武昌区东湖路115号 邮编:430071