卵巢早衰与PGRMC1基因的相关性研究及中药治疗规律分析

发布时间：2018-05-21 21:09

本文选题：卵巢早衰(POF) + 孕激素受体膜组分(PGRMC1)　；参考：《山东大学》2016年博士论文

【摘要】：第一部分卵巢早衰与PGRMC1基因的相关性研究研究背景卵巢早衰(POF)病因尚不明确,约30%的卵巢POF患者发病与遗传因素有关,颗粒细胞凋亡致卵泡闭锁过多是卵巢早衰发病的一个重要机制。越来越多的参与卵泡发育过程的基因被证实与POF发病相关,如GDF9、FOX03、NOBOX、FIGLA、FMR1、FMR2、BMP15、NR5A1以及POU5F1。尽管在某一种族中只有1-2%的人群的某个候选基因会显示异常,但这些异常的级联反应可能会导致卵巢功能的受损。因此,对候选基因进一步筛查对最终建立一个目标图谱是很必要的。孕激素受体膜组分基因(PGRMC1)高表达于啮齿类和灵长类动物卵巢的颗粒细胞和黄体细胞上,能通过对凋亡相关基因表达的调节影响卵泡发育并调整颗粒细胞周期。PGRMC1基因敲除小鼠的卵巢窦卵泡数减少,闭锁的窦卵泡比例升高,提示PGRMC1可能是卵巢早衰发病的一个重要候选基因。在瑞典的临床研究中发现,PGRMC11与女性生殖功能相关。PGRMC1基因是POF的理想候选基因,但目前尚未有PGRMC1与汉族人群POF相关性的研究。目的筛查汉族人群POF患者PGRMC1基因的突变情况,探讨PGRMC1基因变异是否与POF发病相关。方法研究对象为196例就诊于山东大学附属生殖医院的汉族POF患者,对照组为200例同期就诊的卵巢功能正常的汉族女性。抽取研究对象及对照组的外周血,并提取全基因组DNA,采用聚合酶联反应(PCR)技术扩增PGRMC1基因的3个外显子,直接测序分析。结果直接测序后在PGRMC1的第3外显子发现1个新发错义突变(C.556CT,p. Pro186Ser),及一个新发SNP (C.533CT, p. Trh177Ile)。应用PolyPhen-2进行功能预测,p.Pro186Ser得分为0.021,被认为无损于蛋白功能。新发SNP (C.533CT,p. Trh177I1e)在POF组和对照组中比较,无显著性差异。结论PGRMC1是卵巢早衰的一个理想候选基因,但不是汉族人群POF发病的普遍原因。第二部分：基于《中医方剂大辞典》的卵巢早衰用药规律分析研究背景目前卵巢早衰的治疗以激素替代为主,患者依从性较差。中医药治疗辨证论治、防治结合,具有很大的优势。祖国传统医学将卵巢早衰归为“闭经”、“经水早断”范畴,自古文献中就有记载,且流传下许多有效方剂。祖国传统医学讲求辨证、立法、组方施治,其证-法-方之间有密切的逻辑关系,随着样本量的增大,这种逻辑关系必然呈现出一定规律性,发掘其中的规律性是促进中医药信息结构化的途径之一。1997年由人民卫生出版社出版的彭怀仁教授主编的《中医方剂大辞典》是目前资料最全、载方最多、考证和体例最为完善的方剂词典,收录自秦汉时期到1986年底计1800余种中医药文献记载的96592首方剂,成为历代方书整理方面的集大成者。本研究拟选取《中医方剂大辞典》作为方剂基本信息来源,通过对493首与卵巢早衰相关的方剂的组方规律进行研究,分析对自秦汉到当代,治疗治疗卵巢早衰类似证的核心药物、药对及组方规律,并深入挖掘其理、法、方、义,以期为临床工作提供指导。目的运用文献学方法学结合方药统计分析方法研究《中医方剂大辞典》中治疗闭经及经水早断的核心药物、常用药对及药物组合,探寻其性味归经规律及组方规律,根据这些规律衍化出高效新方。方法建立Excel表,录入《中医方剂大辞典》中治疗闭经、经水早断的方剂493首的方剂编号、名称、药物组成,将数据标准化,录入“中医传承辅助系统”,通过软件集成的药物频次统计、用药模式、规则分析等功能,对所选方剂的所有药物进行统计,探讨治疗卵巢早衰的核心药物、常用药对、药物组合并推演出新方；对出现频次大于等于16的60味中药进行性味归经及功效归类统计,从药性理论角度总结用药规律及立法规则的精华。结果1.古代中医治疗卵巢早衰的核心药物是当归、川芎、大黄、肉桂、桃仁、白芍、赤芍、甘草、牡丹皮、牛膝、熟地黄、香附、红花、白术、茯苓、生地黄、延胡索、水蛭、莪术、柴胡、陈皮、虻虫、人参、木香、黄芩、三棱、干漆、桂枝、琥珀、没药、青皮、枳壳、干姜、鳖甲、附子、土瓜根、芫花、芒硝、斑蝥、白芷、砂仁、黄芪、硇砂、麝香、五灵脂、半夏、蒲黄、小茴香、细辛、吴茱萸、凌霄花、麦冬、乌药、当归尾、刘寄奴、知母、苏木、山药、槟榔、益母草。2.最常用的药物包括,活血化瘀药：川芎、桃仁、牛膝、红花、延胡索、水蛭、莪术、虻虫、三棱、没药；补益药：当归、赤芍、甘草、熟地、白术、人参、鳖甲、黄芪、麦冬、当归尾;行气药：香附、陈皮、木香、青皮、枳壳、乌药；温里药：肉桂、干姜、附子、小茴香、吴茱萸；清热药：赤芍、丹皮、生地、黄芩、知母。3. 行之有效的药物组合包括川芎+当归+白芍；川芎+甘草+当归；熟地黄+川芎+当归；熟地黄+当归+白芍；赤芍+川芎+当归；牡丹皮+川芎+当归；甘草+当归+白芍；川芎+当归+香附；赤芍+当归+肉桂；熟地黄+川芎+白芍等。4.核心药物的性味以辛温、苦寒、甘平为主,归经以肝、脾、心、肾为主,核心药物功效归类以活血化瘀药、补虚药、行气药、温里药、清热药为主,常用药对及药药配伍活血化瘀药加用温里药。5.以方测证,气滞血瘀、气血虚弱、肝肾不足、心肾不交是卵巢早衰的基本病机。6.当把相关度设为8,惩罚度设为2,可得到推演新方28个,根据专业知识进行筛选,可得到新方8个,如可用于气滞血瘀证的凌霄花_刘寄奴_苏木_白芷,刘寄奴_肉桂_赤芍_牛膝_桃仁,红花_当归_赤芍_当归尾；可用于气血虚弱证的益母草_紫苏_阿胶_橘红,当归_赤芍_白芍_白术_甘草,白术_茯苓_陈皮_甘草_人参_白芍；可用于肝肾不足证的枸杞子_柏子仁_覆盆子_菟丝子_党参_仙茅；可用于心肾不交证的地骨皮_知母_麦冬_茯神。结论气滞血瘀、肝肾不足、气血虚弱、心肾不交是卵巢早衰的基本病机,治疗以活血化瘀、补益、调整气血阴阳为原则。卵巢早衰的发病与肝、脾、心、肾关系密切,尤其是肝脏,阴血耗伤、肝血亏虚是卵巢早衰的早期病机,应在未病之时或疾病的初起阶段注意保护肝阴,在平时的生活中应注意起居有节、饮食得当、心情舒畅,以防患于未然。
[Abstract]:PGRMC1 gene ( PGRMC1 ) is a promising candidate gene for the pathogenesis of premature ovarian failure . Conclusion PGRMC1 is an ideal candidate gene for premature ovarian failure , but it is not a common cause of the development of Chinese medicine . Conclusion PGRMC1 is an ideal candidate gene for premature ovarian failure . Through the functions of the software integration , the drug frequency statistics , the medication mode , the rule analysis and so on , all the medicines of the selected prescription are counted , the core medicine for treating premature ovarian failure , the common use pair and the drug combination are discussed and the new prescription is deduced ;
A Chinese medicinal composition for treating premature ovarian failure is prepared from Radix Angelicae Sinensis , Rhizoma Chuanxiong , Radix Et Rhizoma Rhei , Cortex Cinnamomi , Semen Persicae , Radix Paeoniae Alba , Radix Paeoniae Rubra , Glycyrrhrizae Radix , Cortex Moutan , Achyranthis Radix , Radix Rehmanniae Preparata , Radix Glycyrrhizae , Cortex Moutan , Hirudo , Radix Rehmanniae Preparata , Radix Bupleuri , Pericarpium Citri Tangerinae , Hirudo , Radix Ginseng , Radix Bupleuri , Pericarpium Citri Tangerinae , Hirudo , Fructus Aurantii , Radix Bupleuri , Myrrha , Radix Aconiti Lateralis Preparata , Fructus Aurantii , Rhizoma Zingiberis , Natrii Sulfas , Radix Aconiti Lateralis Preparata , Fructus Aurantii , Flos Genkwa , Natrii Sulfas , Mylabris , Radix Angelicae Dahuricae , Fructus Amomi , Radix Astragali , and Sal Ammoniacus . Moschus , Oletum Trogopterori , Rhizoma Pinelliae , Pollen Typhae , Fructus Fructus , Herba Asari , Fructus Corni , Flos Campsis , Radix Ophiopogonis , Radix Linus , Radix Angelicae Sinensis , Herba Artemisiae Scopariae , Rhizoma Anemarrhenae , Lignum Sae , Rhizoma Dioscoreae , Semen Penang , and Herba Leonuri . The most commonly used medicines include : Rhizoma Ligustici Chuanxiong , Semen Persicae , Achyranthis Radix , Carthami Flos , Rhizoma Corydalis , Hirudo , Curcumae Rhizoma , Tabanus , Rhizoma Rhizoma , and Myrrha ;
The Chinese medicinal composition is prepared from Radix Angelicae Sinensis , Radix Paeoniae Rubra , Glycyrrhrizae Radix , Radix Rehmanniae Preparata , Atractylodis Rhizoma , Ginseng Radix , Carapax et Radix , Radix Astragali , Radix Ophiopogonis , and Radix Angelicae Sinensis ; and Myrrha , Rhizoma Cyperi , Pericarpium Citri Tangerinae , Radix Aucklandiae , Pericarpium Citri Reticulatae Viride , Fructus Aurantii , and Radix Linus ;
warm medicine : cinnamon , dried ginger , aconite , fennel and evodia ;
Heat - clearing herbs : Radix Paeoniae Rubra , Cortex Moutan , Radix Rehmanniae , Scutellariae Radix , and Rhizoma Anemarrhenae . The effective drug combination comprises Rhizoma Ligustici Chuanxiong , Radix Angelicae Sinensis and Radix Paeoniae Alba ;
Rhizoma Ligustici Chuanxiong , Glycyrrhrizae Radix and Radix Angelicae Sinensis ;
Radix Rehmanniae Preparata , Rhizoma Ligustici Chuanxiong and Radix Angelicae Sinensis ;
Radix Rehmanniae Preparata , Radix Angelicae Sinensis and Radix Paeoniae Alba ;
Radix Paeoniae Rubra , Rhizoma Ligustici Chuanxiong and Radix Angelicae Sinensis ;
Cortex Moutan , Rhizoma Ligustici Chuanxiong and Radix Angelicae Sinensis ;
Radix Glycyrrhizae , Radix Angelicae Sinensis and Radix Paeoniae Alba ;
Rhizoma Ligustici Chuanxiong , Radix Angelicae Sinensis and Rhizoma Cyperi ;
Radix Paeoniae Rubra , Radix Angelicae Sinensis and Cortex Cinnamomi ;
The medicine is mainly prepared from Radix Rehmanniae Preparata , Rhizoma Ligustici Chuanxiong , Radix Paeoniae Alba and the like .
can be used for qi and blood asthenia syndrome , Herba Leonuri , Perillae Herba , Pericarpium Citri Rubrum , Radix Angelicae Sinensis , Radix Paeoniae Rubra , Radix Paeoniae Alba , Atractylodis Rhizoma , Glycyrrhrizae Radix , Rhizoma Atractylodis Macrocephalae , Poria , Pericarpium Citri Tangerinae , Glycyrrhrizae Radix , and Radix Paeoniae Alba ;
can be used for the treatment of liver and kidney deficiency syndrome of Fructus Lycii , Semen Cupresae , Rubi Fructus , Semen Cuscutae and Radix Codonopsis ;
Conclusion Qi stagnation and blood stasis , deficiency of liver and kidney , deficiency of qi and blood , heart and kidney are the basic pathogenesis of premature ovarian failure . The pathogenesis of premature ovarian failure is closely related to liver , spleen , heart and kidney .
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R271.9

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