吕社民
①复杂性疾病易感基因的定位与克隆②慢性炎症性疾病的分子发病机理③动物模型的构建和评价
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- 姓名:吕社民
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博士生导师
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生物化学
- 研究兴趣:①复杂性疾病易感基因的定位与克隆②慢性炎症性疾病的分子发病机理③动物模型的构建和评价
吕社民,博士,教授、博士生导师。1982年毕业于西安医学院,获医学学士学位,1988年在西安医科大学获生物化学与分子生物学专业医学硕士学位,2002年2月在瑞典Lund大学获分子免疫学与遗传学博士学位。1982年12月至1995年9月在西安医科大学地方性骨病研究所,历任研究实习员、助理研究员、副研究员,研究所副所长兼生化研究室主任。1995年l0月至2004年9月,在瑞典Lund大学医学院医学炎症研究所以高级访问学者及博士后研究人员从事研究工作,2004年6月被西安交通大学聘任为生物化学与分子生物学教授;2005年1月任遗传学与分子生物学系系主任。兼任医学院学术委员会委员,陕西省生物化学与分子生物学学会副理事长,陕西省基础医学生物化学与分子生物学专业委员会主委。作为主要完成人参与“八五”国家攻关课题“低硒及有关因素在克山病、大骨节病病因中的作用比较研究”(85-917-01-02/03); “Rat genome project ; EU project”; “RA genetics; EU project ”; “Genetics inflammatory diseases; genome initiative – application.”等。主持“Identifying genes in MHC regions to regulate arthritis development in rats supported by the Anna Creta Crafoord Foundation for Rheumatotologicval Research”; 现承担国家自然科学基金、教育部留学回国基金、西安交通大学“985工程”二期生物医学与健康科技创新平台子项目---生物医学资源与模式动物研究中心: 地方病基因-环境相互作用及分子机理研究、学校暨医学院科研启动项目等科研项目。主要研究成果: ①发现了大骨节病区儿童硒代谢的不平衡;②通过硒负荷试验表明大骨节病区儿童存在着硒缺乏;“硒与大骨节病研究”(集体成果奖)获1996年度国际生物无机科学家协会授予的KLAUS SCHWARZ奖; ③克隆了大鼠关节炎的致病基因——Ncf1; ④首次创建新的类风湿关节炎动物模型—NOCIA(Non-oil Collagen Induced Arthritis)和支气管哮喘的动物模型—AIPI(Antigen Induced Pulmonary Inflammation); ⑤定位了数十个大鼠关节炎易感位点。已发表学术论文80余篇。研究方向:①复杂性疾病易感基因的定位与克隆②慢性炎症性疾病的分子发病机理③动物模型的构建和评价。
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【期刊论文】A Modified Method using TRIzol
吕社民, Dongmin Li & Wuchao Ren & Xuan Wang & Feimiao Wang & Yu Gao & Qilan Ning & Yan Han & Tianbao Song & Shemin Lu
,-0001,():
-1年11月30日
To establish an economical and reproducible method for the high-quality RNA extraction from pancreas, we isolated total RNA from rat pancreas with TRIzol
Rat pancreas, RNA., Total RNA extraction, TRIzol
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吕社民, Muhammad Shahzad a, b, Xudong Yang a, M.B. Raz a Asim a, Qingzhu Sun a, Yan Han a, Fujun Zhang a, Yongxiao Cao a, c, Shemin Lu a, *
Pulmonary Pharmacology & Therapeutics 22(2009)37-43,-0001,():
-1年11月30日
The black seeds, from the Ranunculaceae family, have been traditionally used by various cultures as a natural remedy for several ailments. In this study, we examined the effect of black seed oil as an immunomodulator in a rat model of allergic airway inflammation. Rats sensitized to ovalbumin and challenged intranasally with ovalbumin to induce an allergic inflammatory response were compared to ovalbumin-sensitized, intranasally ovalbumin-exposed rats pretreated with intraperitoneally administered black seed oil and to control rats. The levels of IgE, IgG1 and ova-specific T-cell proliferation in spleen were measured by ELISA. The pro-inflammatory cytokine IL-4, IL-5, IL-6 and TGF-b1 mRNA expression levels were measured by reverse transcription polymerase chain reaction. The intraperitoneal administration of black seed oil inhibited the Th2 type immune response in rats by preventing inflammatory cell infiltration and pathological lesions in the lungs. It significantly decreased the nitric oxide production in BALF, total serum IgE, IgG1 and OVA-specific IgG1 along with IL-4, IL-5, IL-6 and TGF-b1 mRNA expression. Black seed oil treatment resulted in decreased T-cell response evident by lesser delayed type hypersensitivityand lower T-cell proliferation in spleen. In conclusion, black seed oil exhibited a significant reduction in all the markers of allergic inflammation mainly by inhibiting the delayed type hypersensitivity and T-cell proliferation. The data suggests that inhibition of T-cell response may be responsible for immunomodulatory effect of black seed oil in the ratmodel of allergic airway inflammation.
Black seed oil, Delayed type hypersensitivity, E3 rats, IgE, IgG, Nitric oxide, T-cell proliferation
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【期刊论文】用动物模型定位、克隆复杂性疾病的易感基因:以类风湿关节炎动物模型为范例
吕社民
,-0001,():
-1年11月30日
基于复杂性疾病的临床异质性,或称表型异质性;遗传异质性,或称位点异质性;多基因的微效作用;异位显性(epistasis);拟表型(phenocopy);环境因素的作用等特点,鉴定复杂性疾病的易感基因是一种艰巨有时难以完成的任务。近交系动物遗传背景清晰,动物实验可控制环境因素的干扰,以及转基因动物在研究基因功能中独特的作用,应用动物模型为筛选鉴定人类复杂性疾病的易感基因提供了不可替代的工具。以大鼠类风湿关节炎模型为例,定位克隆易感基因步骤包括: (1)选择亲代近交系, 建立关节炎模型; (2)分离育种,连锁分析、确定数量性状位点(QTLs);(3)建立Congenic系、窄化QTL区域;(4)位置克隆基因;(5)易感基因的功能验证。我们应用这一策略从朴日斯烷(Pristane)诱导的关节炎大鼠模型中已筛选出十余个控制关节炎发生发展的非MHC基因位点,在此基础上克隆的Pia4基因被鉴定为是中性粒细胞胞浆因子1(Ncf1),说明此一研究策略是完全可行的,并且可能发现新的功能基因或已知基因的新功能。
复杂性疾病, 关节炎, 易感基因, 动物模型
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吕社民, Balik Dzhambazov, Meirav Holmdahl, Hisakata Yamada, Shemin Lu, Mikael Vestberg, Bj rn Holm, Olof Johnell, Jan Kihlberg and Rikard Holmdahl
Eur. J. Immunol. 2005. 35: 1-10,-0001,():
-1年11月30日
Type II collagen (CII) is a target for autoreactive Tcells in both rheumatoid arthritis and the murine model collagen-induced arthritis. The determinant core of CII has been identified as CII260-270, and the alteration of this T cell epitope by posttranslational modifications is known to be critical for development of arthritis in mice. Using CIIspecific Tcell hybridomas we have now shown that the immunodominant Tcell epitope in the normal (healthy) human and rat joint cartilage is O-glycosylated at the critical T cell receptor recognition position 264 with a mono- or di-saccharide attached to a hydroxylysine. In contrast, in the arthritic human and rat joint cartilage there are both glycosylated and non-glycosylated CII forms. Glycosylated CII from normal cartilage could not be recognized by T cells reactive to peptides having only lysine or hydroxylysine at position 264, showing that antigen-presenting cells could not degrade the O-linked carbohydrate. Thus, the variable forms of the glycosylated epitope are determined by the structures present in cartilage, and these vary during the disease course. We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states.
Arthritis, CII, Glycosylation, Processing, APC
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吕社民, Peter Olofsson, , Shemin Lu, Jens Holmberg, Tusheng Song, Patrik Wernhoff, Ulf Pettersson, . and Rikard Holmdahl
ARTHRITIS & RHEUMATISM Vol. 48, No.8, August 2003, pp 2332-2342,-0001,():
-1年11月30日
Objective. To compare the genetic regulation of collagen-induced arthritis (CIA) with that of pristaneinduced arthritis (PIA) in rats. Methods. A genome-wide linkage analysis of an (E3 DA)DA backcross of rats with CIA (n 364 male rats; the same strain combinations as previously used to determine the genetic control of PIA) was performed. The strongest loci in both CIA and PIA (i.e., Cia12/Pia4 and Cia13/Pia7) were isolated in congenic strains. Susceptibility in both congenic strains was tested in rats with CIA and in rats with PIA. Results. We found a striking, although not complete, similarity of the arthritis-controlling loci in CIA and in PIA, as well as the previously defined loci associated with cartilage destruction, antibody production, and the acute-phase response. All major PIA quantitative trait loci (QTLs) identified in early severe arthritis were also strong regulators of CIA. The 2 strongest QTLs, Cia12/Pia4 on chromosome 12 and Cia13/Pia7 on chromosome 4, were also analyzed in congenic strains with DA or E3 as the background genome. Consistent with the results of linkage analysis, the congenic strain experiments showed that the chromosome 4 locus was more penetrant in CIA than in PIA, while the chromosome 12 locus almost completely dominated the control of PIA severity. Conclusion. The underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage-specific antigen (type II collagen) to induce CIA but not PIA.
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吕社民, Shemin Lu, Stefan Carlsen, Ann-Sofie Hansson and Rikard Holmdahl
Joumal of Autoimmunity (2002) 18, 199-211,-0001,():
-1年11月30日
The most commonly used animal model for rheumatoid arthritis (RA) is collagen-induced arthritis (CIA), induced by immunization with type II collagen (CII), a cartilage restricted protein. In this work we show that type XI collagen (CXI), which is a minor component in cartilage, induces a different form of erosive and chronic relapsing polyarthritis in rats. Using a series of inbred rat strains involving various genetic backgrounds (DA, LEW, E3), and congenic MHC regions (a, u, f, n, c, d), we found that CXI induced arthritis (CXIIA) is associated with the RT1f haplotype in contrast to CII induced arthritis (CIIIA), which is associated with the RT1a and RT1u haplotypes. The CXIIA follows a chronic disease course affecting peripheral joints with both progression and relapses, which appear not to cease (occurring >800 days). Susceptible strains showed a sustained antibody response to CXI with time indicating that the autoimmune response was self-perpetuated. Microscopic analysis of the joints at different stages demonstrated the severe destruction of bone and cartilage by pannus tissue consisting of activated macrophages and T cells. The main difference to joints from rats with CIIIA was larger numbers of infiltrating lymphocytes and these tended to form follicle-like aggregates. Surprisingly, males were more susceptible to CXIIA than females whereas the opposite has been observed in other rat arthritis models, including CIIIA. Taken together, CXIIA is a chronic relapsing and erosive polyarthritis that is MHC associated, which in fact fulfills the criteria for diagnosis of RA. Thus the CXIIA model will be useful as a novel and relevant animal model for RA.
collagen type XI,, induced arthritis,, major histocompatibility complex,, rats,, rheumatoid arthritis
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吕社民, Peter Olofsson, a,
Genomics 83(2004)765-771,-0001,():
-1年11月30日
We recently identified a single-nucleotide polymorphism in the Ncf1 gene, a component of the NADPH oxidase complex, to be the cause of one of the strongest identified loci for arthritis severity in rats. This polymorphism was found to be naturally occurring in a collection of inbred rat strains as well as in wild rats. Among the inbred strains we found that different LEW substrains (LEW/Ztm and LEW/Mol), originating from different breeders, showed an allelic discrepancy in Ncf1, suggesting an impact on arthritis susceptibility between these substrains. In fact, the LEW/Mol strain was completely resistant to pristane-induced arthritis, in contrast to the LEW/Ztm strain, which was susceptible. Moreover, the LEW/Mol strain had higher production of radical oxygen species in peripheral blood leukocytes, a phenomenon most likely regulated by the polymorphisms in the Ncf1 gene. However, the phenotypic difference between LEW/Mol and LEW/Ztm is most likely a combination of several genes, of which Ncf1 is suggested to be the major regulating gene. This has also been confirmed by previous linkage analyses involving the LEW/Ztm strain which shows that a QTL on chromosome 12, most likely caused by polymorphism of Ncf1, is the major regulatory gene but that other loci are contributing. That more genes are likely to contribute was shown by a complete genome comparison of the LEW/Ztm and the LEW/Mol rat strains that uncovered an introduction of approximately 37% non-LEW genome into the LEW/Mol strain, which probably was caused by past crossbreeding. Therefore, the LEW/Mol should be regarded as a recombinant inbred strain.
Arthritis, Ncƒ1, Inbred rats, Pristane-induced arthritis, Linkage analysis, LEW inbred rat strain
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吕社民, A-S. HANSSON, S. LU & R. HOLMDAHL Medical Inflammation Research, Biomedical Center, Lund University, Lund, Sweden
Clin Exp Immunol 2002; 127: 37-42,-0001,():
-1年11月30日
Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting cartilaginous joints but also extra-articular tissues such as the nose and upper respiratory tract. We have investigated extraarticular cartilage involvement in two commonly used animal models for RA, collagen-induced and pristane-induced arthritis, by immunizing rats with different susceptibility to disease (LEW.1A, LEW.1F and DA rats). We found that nasal and tracheolaryngeal cartilage is affected in LEW.1 A and DA rats to varying degrees in collagen-induced arthritis but not in any strain in the pristane-induced model. Antibodies to matrilin-1, a cartilage-specific protein expressed mainly in tracheolaryngeal and nasal cartilage but not in joints, were positively associated with the presence of inflammation in nasal cartilage. In contrast, no antibody response to matrilin-1 could be detected in pristane-induced arthritis. In addition, nasal vaccination with collagen type II prior to immunization in DA rats significantly decreased the antibody response to matrilin-1 at day 56, but not at earlier time points, indicating a late protective effect on extra-articular cartilage. We conclude that pristane-induced arthritis is a jointspecific model whereas collagen-induced arthritis affect joints as well as extra-articular cartilage. Furthermore, collagen immunization induces an antibody response to matrilin-1.
arthritis CIA collagen matrilin-1 PIA
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吕社民, Shemin Lu*, , Niklas Nordquist, Jens Holmberg, Peter Olofsson, Ulf Pettersson and Rikard Holmdahl
European Journal of Human Genetics (2002) 10, 475-483,-0001,():
-1年11月30日
Pristane-induced arthritis (PIA) in rats is an animal model for rheumatoid arthritis (RA). We have previously identified seven quantitative trait loci (QTLs), which regulate arthritis development using a cross between the susceptible DA strain and the resistant E3 strain of rats (Pia2-8). In the present study the inbred rat strain LEW.1F was used as the susceptible strain in a cross with the E3 strain. The results confirmed the locus Pia4 on chromosome 12, which previously was shown to be associated with PIA, and also with experimental allergic encephalomyelitis, in crosses between the rat strains E3 and DA. On chromosome 1, linked to the albino locus, we identified a novel QTL, Pia9 in the LEW.F1 cross. This locus was associated with arthritis severity in the early phase of disease. A locus on chromosome 16, denoted Pia11, was also associated with arthritis severity in the early phase of the disease. A suggestive locus was detected on chromosome 14, which was associated with arthritis severity at the time when PIA progresses into a chronic phase. Using a congenic LEW.1F strain, which carries E3 alleles at the Pia9 locus, we confirmed that the E3 allele significantly suppresses arthritis severity during the early phase of the disease. The results revealed synergistic effects between different susceptibility loci using ANOVA analysis. These interactions were influenced by gender. Rats with Pia9 alleles from LEW.1F and Pia11 alleles from E3, were shown to suffer from much more severe arthritis in the early stage of the disease. On the other hand, the Pia 9 and the suggestive locus on chromosome 14 affected only males during the chronic phase of the disease. These findings provide clues to how genetic factors by themselves, and in interaction with each other, regulate the development of a disease, which displays many similarities to RA.
pristane-induced arthritis, rheumatoid arthritis, QTL, rats, linkage, autoimmune disease, genetics
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