脂质转染构建Graves病小鼠模型及~(11)C-CFT PET纹状体显像
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摘要
Graves病是最常见的良性甲状腺疾病之一,其发病涉及自身免疫机制,具有较高的研究价值。Graves病动物模型研究近年虽有长足的进步,目前仍缺乏便捷、经济、高效的建模方法。甲状腺功能异常常与情绪状态相关,而多巴胺系统是主要的情绪调节系统。本研究尝试用脂质转染的方法构建Graves病动物模型,并探索其最优化条件,此外亦对Graves病模型小鼠多巴胺系统11C-CFT PET显像的可能性进行了初步探讨。
本研究主要分两部分。第一部分用不同质粒、目的基因与转染频率的组合来免疫小鼠,结合其体重、甲状腺激素及促甲状腺激素受体(TSHR)抗体(TRAbs)水平的变化,选取诱导率最高的组合。结果提示,使用pUBC作为载体时,无论TSHR还是TSHR A亚基(THRA)基因作为目的基因,都无法获得良好的诱导率。使用pCDNA3.1(+)时,小鼠的体重、甲状腺激素及TRAbs水平变化均较符合预期,若目的基因为THRA亚基且提高转染前期的转染频率,则可获得最好的诱导成功率。
第二部分在第一部分成功构建模型的基础上,选取以pCDNA3.1(+)为载体免疫的两组中各8只具有代表性的小鼠,尝试通过11C-CFT PET比较其与对照组小鼠纹状体多巴胺系统功能差异。结果提示模型组小鼠纹状体多巴胺转运体活性较对照组下降,下降程度与游离甲状腺素水平负相关。
综合以上两部分结果,本研究揭示了一种经济有效的构建小鼠Graves病模型的方法,并初步提示了用分子影像学手段研究该模型小鼠纹状体多巴胺系统功能改变的可行性。
Graves'disease is a common and autoimmune related thyroid disease, yet some of its features remain enigmatic. There has been a major improvement in the devel-opment of animal models of Graves'disease, but none of them has been proved to be applicable, economic and effective. Further more, abnormal thyroid function is often related to emotional state, which per se is regulated by the striatum dopaminergic system. In our study, lipofection was employed to induce mouse model of Graves' disease, and the best combination of its components was researched. Besides, possi-bility of detecting changes in striatum dopaminergic function in these animal models was also covered.
There was two main parts of this study. The first part used different combina-tions of plasmid vectors, target genes and frequency of transfection to induce Graves disease. Changes of animal weight, thyroid hormone levels and levels of anti-thyroid hormone receptor (TSHR) antibodies (TRAbs) were compared with control group. The result suggested that either genes encoding TSHR or TSHR A subnit (THRA) was employed, no sufficient Graves'disease was induced by using the vector pUBC. On the contrary, when pCDNA3.1(+) was used as the vector, sufficient Graves'dis-ease was induced in both groups using TSHR and THRA subunit as target genes, the latter with an even higher effective rate. Further more, more frequent transfection in the early period was proved to be beneficial.
In the second part,8representative animals in each group (pCDNA3.1(+)-TSHR, pCDNA3.1(+)-TSHRA and control) were enrolled.11C-CFT PET was used to evaluate changes in striatum dopaminergic function between these groups. Accord-ing to relatively small sample size, no statistical analysis was carried out effectively, but we can still find some clue that animals transfected with genes of TSHR or THRA subunit had lower activity of striatum dopamine transporter, and the extent was inversely correlated to serum free T4level.
In brief, an economic and effective method to develop Graves'disease in mouse was introduced in this study, and using molecular imaging as a tool for evaluating changes in striatum dopaminergic function in this model was proved to be applicable.
本研究主要分两部分。第一部分用不同质粒、目的基因与转染频率的组合来免疫小鼠,结合其体重、甲状腺激素及促甲状腺激素受体(TSHR)抗体(TRAbs)水平的变化,选取诱导率最高的组合。结果提示,使用pUBC作为载体时,无论TSHR还是TSHR A亚基(THRA)基因作为目的基因,都无法获得良好的诱导率。使用pCDNA3.1(+)时,小鼠的体重、甲状腺激素及TRAbs水平变化均较符合预期,若目的基因为THRA亚基且提高转染前期的转染频率,则可获得最好的诱导成功率。
第二部分在第一部分成功构建模型的基础上,选取以pCDNA3.1(+)为载体免疫的两组中各8只具有代表性的小鼠,尝试通过11C-CFT PET比较其与对照组小鼠纹状体多巴胺系统功能差异。结果提示模型组小鼠纹状体多巴胺转运体活性较对照组下降,下降程度与游离甲状腺素水平负相关。
综合以上两部分结果,本研究揭示了一种经济有效的构建小鼠Graves病模型的方法,并初步提示了用分子影像学手段研究该模型小鼠纹状体多巴胺系统功能改变的可行性。
Graves'disease is a common and autoimmune related thyroid disease, yet some of its features remain enigmatic. There has been a major improvement in the devel-opment of animal models of Graves'disease, but none of them has been proved to be applicable, economic and effective. Further more, abnormal thyroid function is often related to emotional state, which per se is regulated by the striatum dopaminergic system. In our study, lipofection was employed to induce mouse model of Graves' disease, and the best combination of its components was researched. Besides, possi-bility of detecting changes in striatum dopaminergic function in these animal models was also covered.
There was two main parts of this study. The first part used different combina-tions of plasmid vectors, target genes and frequency of transfection to induce Graves disease. Changes of animal weight, thyroid hormone levels and levels of anti-thyroid hormone receptor (TSHR) antibodies (TRAbs) were compared with control group. The result suggested that either genes encoding TSHR or TSHR A subnit (THRA) was employed, no sufficient Graves'disease was induced by using the vector pUBC. On the contrary, when pCDNA3.1(+) was used as the vector, sufficient Graves'dis-ease was induced in both groups using TSHR and THRA subunit as target genes, the latter with an even higher effective rate. Further more, more frequent transfection in the early period was proved to be beneficial.
In the second part,8representative animals in each group (pCDNA3.1(+)-TSHR, pCDNA3.1(+)-TSHRA and control) were enrolled.11C-CFT PET was used to evaluate changes in striatum dopaminergic function between these groups. Accord-ing to relatively small sample size, no statistical analysis was carried out effectively, but we can still find some clue that animals transfected with genes of TSHR or THRA subunit had lower activity of striatum dopamine transporter, and the extent was inversely correlated to serum free T4level.
In brief, an economic and effective method to develop Graves'disease in mouse was introduced in this study, and using molecular imaging as a tool for evaluating changes in striatum dopaminergic function in this model was proved to be applicable.
引文
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[21]CHEN C R, PICHURIN P, CHAZENBALK G, et al. Low-dose immuniza-tion with adenovirus expressing the thyroid-stimulating hormone receptor A-subunit deviates the antibody response toward that of autoantibodies in human Graves'disease.[J]. Endocrinology,2004,145(1):228-233. http://dx.doi.org/ 10.1210/en.2003-1134.
[22]KANEDA T, HONDA A, HAKOZAKI A, et al. An improved Graves'disease model established by using in vivo electroporation exhibited long-term immunity to hyperthyroidism in BALB/c mice.[J]. Endocrinology,2007,148(5):2335-2344. http://dx.doi.org/10.1210/en.2006-1077.
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[2]RASTOGI R, LAPIERRE Y, SINGHAL R. Diazepam modifies L-triiodothyronine-stimulated changes in behaviour and the metabolism of brain norepinephrine, dopamine and 5-hydroxytryptamine-a possible mechanism of ac-tion.[J]. Journal of psychiatric research,1979,15(1):7-20.
[3]CROCKER A, OVERSTREET D. Modification of the behavioural effects of haloperidol and of dopamine receptor regulation by altered thyroid status. [J]. Psychopharmacology,1984,82(1-2):102-106.
[4]CROCKER A, OVERSTREET D, CROCKER J. Hypothyroidism leads to in-creased dopamine receptor sensitivity and concentration.[J]. Pharmacology, bio-chemistry, and behavior,1986,24(6):1593-1597.
[5]CROCKER A, CAMERON D. Evidence for post-synaptic changes mediating increased behavioural sensitivity to dopamine receptor agonists in hypothyroid rats.[J]. Progress in neuro-psychopharmacology & biological psychiatry,1988, 12(5):607-615.
[6]CAMERON D, CROCKER A. The hypothyroid rat as a model of increased sensitivity to dopamine receptor agonists. [J]. Pharmacology, biochemistry, and behavior,1990,37(4):627-632.
[7]SRIWATANAKUL K, MCCORMICK K, WOOLF P. Thyrotropin (TSH)-induced hyperthyroidism:response of TSH to dopamine and its agonists.[J]. The Journal of clinical endocrinology and metabolism,1984,58 (2):255-261.
[8]VALLORTIGARA J, ALFOS S, MICHEAU J, et al. T3 administration in adult hypothyroid mice modulates expression of proteins involved in striatal synap- tic plasticity and improves motor behavior. [J]. Neurobiology of disease,2008, 31(3):378-385. http://dx.doi.org/10.1016/j.nbd.2008.05.015.
[9]SCHLENKER E H, SCHULTZ H D. Hypothyroidism attenuates SCH 23390-mediated depression of breathing and decreases dl receptor expression in carotid bodies, PVN and striatum of hamsters[J]. Brain Research,2011,1401:40-51. http://www.ncbi.nlm.nih.gov/pubmed/21669406. PMID:21669406.
[10]SCHLENKER E, SCHULTZ H. Hypothyroidism stimulates D2 receptor-mediated breathing in response to acute hypoxia and alters D2 receptors levels in carotid bodies and brain.[J]. Respiratory physiology and neurobiology,2012, 180(1):69-78. http://dx.doi.org/10.1016/j.resp.2011.10.013.
[11]林岩松,王卉呈,赵志英,等.实验性甲状腺功能亢进大鼠脑多巴胺转运蛋白及多巴胺含量的变化[J].中华核医学杂志,2009,29(2)：99-102.
[12]OHMORI M, ENDO T, ONAYA T. Development of chicken antibodies toward the human thyrotropin receptor peptides and their bioactivities.[J]. Biochemical and biophysical research communications,1991,174(1):399-403.
[13]ENDO T, OHMORI M, IKEDA M, et al. Thyroid stimulating activity of rabbit antibodies toward the human thyrotropin receptor peptide.[J]. Biochemical and biophysical research communications,1991,177(1):145-150.
[14]COSTAGLIOLA S, ALCALDE L, RUF J, et al. Overexpression of the extracellu-lar domain of the thyrotrophin receptor in bacteria; production of thyrotrophin-binding inhibiting immunoglobulins.[J]. Journal of molecular endocrinology, 1994,13(1):11-21.
[15]COSTAGLIOLA S, MANY M, STALMANS-FALYS M, et al. Recombinant thy-rotropin receptor and the induction of autoimmune thyroid disease in BALB/c mice:a new animal model.[J]. Endocrinology,1994,135(5):2150-2159.
[16]HIDAKA Y, GUIMARAES V, SOLIMAN M, et al. Production of thyroid-stimulating antibodies in mice by immunization with T-cell epitopes of human thyrotropin receptor.[J]. Endocrinology,1995,136(4):1642-1647.
[17]KIKUOKA S, SHIMOJO N, YAMAGUCHI K, et al. The formation of thy-rotropin receptor (TSHR) antibodies in a Graves'animal model requires the N-terminal segment of the TSHR extracellular domain.[J]. Endocrinology,1998, 139(4):1891-1898.
[18]COSTAGLIOLA S, RODIEN P, MANY M, et al. Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of mon-oclonal antibodies recognizing the native receptor. [J]. Journal of immunology (Baltimore, Md.:1950),1998,160(3):1458-1465.
[19]COSTAGLIOLA S, MANY M, DENEF J, et al. Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves'disease.[J]. The Journal of clinical investigation,2000,105(6):803-811. http://dx.doi. org/10.1172/JCI7665.
[20]NAGAYAMA Y, KITA-FURUYAMA M, ANDO T, et al. A novel murine model of Graves'hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor.[J]. Journal of immunology (Baltimore, Md.:1950), 2002,168(6):2789-2794.
[21]CHEN C R, PICHURIN P, CHAZENBALK G, et al. Low-dose immuniza-tion with adenovirus expressing the thyroid-stimulating hormone receptor A-subunit deviates the antibody response toward that of autoantibodies in human Graves'disease.[J]. Endocrinology,2004,145(1):228-233. http://dx.doi.org/ 10.1210/en.2003-1134.
[22]KANEDA T, HONDA A, HAKOZAKI A, et al. An improved Graves'disease model established by using in vivo electroporation exhibited long-term immunity to hyperthyroidism in BALB/c mice.[J]. Endocrinology,2007,148(5):2335-2344. http://dx.doi.org/10.1210/en.2006-1077.
[23]ZHAO S X, TSUI S, CHEUNG A, et al. Orbital fibrosis in a mouse model of Graves'disease induced by genetic immunization of thyrotropin receptor cDNA.[J]. The Journal of endocrinology,2011,210(3):369-377. http://dx. doi.org/10.1530/JOE-11-0162.
[24]WELCH M, KILBOURN M, MATHIAS C, et al. Comparison in animal mod-els of 18F-spiroperidol and 18F-haloperidol:potential agents for imaging the dopamine receptor.[J]. Life sciences,1983,33(17):1687-1693.
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