科研体会.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,科研体会,广州中医药大学生理教研室 徐进文,科研定义,一般是指利用科研手段和装备，为了认识客观事物的内在本质和运动,规律,而进行的调查研究、实验、试制等一系列的活动。,目的与方法,创新性、可行性,雌激素与血管保护,王庭槐 教授,中山医学院生理教研室,Women protected by estrogen?,Men exacerbated by androgen,？,雌激素与血管舒张,在体试验：,ERT,可明显改善绝经后妇女肱动脉血流介导的内皮依赖性舒张功能（高频超声技术测定肱动脉血流）。,Hypertension.2001;37:651-7.,PWM:52,5 years old,CEE,0.625mg/day,12,周,离体试验：,ERT,可明显改善绝经后妇女内皮依赖性舒张功能。,PWM 54,3 years old,，,CEE,0.625mg/day,12,周，,取腹部皮下微血管。,JCEM.2008;90:61136122.,其它机制：,激活内皮细胞中环氧化酶活性，促进前列环素,PGI2,释放。,抑制血管平滑肌细胞,L-,型钙离子通道。,J,Clin,Endocrinol,Metab,.2002;87(11):5072-5075,Eur J Pharmacol.1995;294(2-3):625-635,雌激素抗动脉粥样硬化,动物模型试验：,雌激素可减少粥样斑块形成。,Primates.2003;44(3):247-52.,血管壁的三层结构,内皮的重要功能,Endothelial function,：,Regulation vascular tone and inflammation,anti-coagulation.,雌激素舒张血管主要机制：促进内皮细胞,NO,释放,王庭槐*，杨丹，刘培庆,等,.,生理学报,2000,52(6):479,482,*,*,*,#,#,CON,E2,10,-12,10,-10,10,-8,L-NAME,Tam,CON 1h 16h 48h GADPH Mark,10,-8,M E2,CON 1h 16h 48h +Ta,10,-8,M E2,eNOS,eNOS,雌激素舒血管效应,应用,E2 30mol,后，,Ca2+i,下降到静息电位水平，肌张力也大幅度降低。其下降幅度分别为,97.22.6%,95.53.2%(n=7),。此结果显示雌激素通过拮抗,Ca2+,通道而抑制,Ca2+,内流。,Ap+De,Ap+De,Ap+De,Pro+Pl,Jn,Mb,Pl,Jn,替代治疗前,JCEM.2008;90:61136122.,电子显微镜显示微血管内皮细胞形态结构（,820,倍放大）,Jn,：内皮间连接丧失,Ap,：凋亡,De,：脱落,PI,：血小板聚集,Pro,：蛋白聚集,Mb,：基膜破裂,替代治疗后,血管平滑肌细胞（,VSMC),Proliferation of VSMC in atherosclerosis,MKP-1,Cavolin-1,NO,E2,c-fos,p38MAPK,iNOS,ER,ERK,P21,Cyclin,D,VSMCs,Proliferation inhibition,nucleus,E2,membrane,mER,抑制血管平滑肌细胞增殖,王庭槐等,.,雌激素抑制血管损伤反应的细胞内信号转导机制,1.,Ting,Huai,Wang*,Qiu,Ling,Xiang,Jian,Wen,Chen,Hong Pan and Yu Hong Cui.,Raloxifene,plus 17beta-estradiol inhibits proliferation of primary cultured vascular smooth muscle cells and human mammary endothelial cells via the,janus,kinase,/signal transducer and activator of transcription3 cascade.European Journal of Pharmacology.2007,561:7-13.,2.,Liu HM,Zhao XF,Guo,LN,Tan Z,Wang TH*.Effects of caveolin-1 on the 17beta-estradiol-mediated inhibition of VSMC proliferation induced by vascular injury.Life,Sci,.2006,雌激素抑制血管平滑肌细胞,MCP-1,产生,王庭槐等，,unpublished data,雌激素抑制,NF-,kB,信号，抑制,MCP-1,产生,Control,LPS,LPS+E,2,NF-,kB,p65,亚单位,nucleus,Merge,Jiang,P*,，,Xu,JW*,Zheng,SH,Huang JH,Xiang,QL,Fu XD,Wang TH.17-estradiol Down-regulates LPS-induced MCP-1,Producition,and Cell Migration in Vascular Smooth Muscle Cells.Journal of Molecular Endocrinology.2010,45(2):87-97(*,，,equal contribution).,球囊损伤,球囊损伤,+E2,球囊损伤,球囊损伤,+E2,外膜增殖,内膜增生,雌激素（,应用,7d,）抑制血管损伤后外膜增殖和新生内膜形成,雌激素抑制血管外膜增殖,王庭槐等,中华老年心血管病杂志,.,2005,7(5):337-340,不同时间点给予雌激素对球囊损伤后外膜形成的影响,Thickness,王庭槐等,中国老年保健医学,.,2006,4(1):19-22,王庭槐等,中华老年心血管病杂志,.,2006,8(2):122-125,研究目的：评价绝经后妇女长期应用雌、孕激素连续联合补充治疗的受益,/,风险化。,研究对象：,50-79,岁的,27347,名绝经后美国妇女，平均年龄为,63,岁。,时间：,1991,年启动，,1993,年招募受试者，计划观察,15,年。,试验分组：,单纯应用雌激素,(ERT),组，对象为已做过子宫切除术的妇女,倍美力,0.625mg,雌、孕激素连续联合治疗,(HRT),组,倍美力,0.625mg+,安宫黄体酮,2.5mg,安慰剂组,服用安慰剂,WHI:,激素替代疗法与冠心病,Stopped at 5.2 years,Stopped at 7 years,E Study,主要结果,E,P(2002),E(2004),CHD,1.29,(1.02-1.63),0.91(0.75-1.12),Breast cancer,1.26,(1.00-1.59),0.77(0.59-1.01),Stroke,1.41,(1.07-1.85),1.39,(1.10-1.77),Pulmonary embolism,2.13,(1.39-3.25),1.34,(0.87-2.06),Endometrial cancer,0.63(0.43-0.92),Coloretal,cancer,0.83(0.47-1.47),1.08(0.75-1.55),Hip fracture,0.66(0.45-0.98),0.61(0.41-0.91),Other death,0.92(0.74-1.14),对,WHI,结果解析,样本人群年龄偏高。,孕激素是否对雌激素的作用产生干扰？,雌激素的剂量问题。,人群的依从性问题。,雌激素的给药方式问题。,王庭槐教授谈雌激素替代疗法的应用,.,保健医苑,2002,年，第五期，第六期连载,Coronary Heart Disease in WHI:Later Analysis,Arch Intern Med 2006,Coronary Heart Disease in WHI:Later Analysis,Arch Intern Med 2006,Coronary Heart Disease in WHI:Later Analysis,Arch Intern Med 2006,20,HAZARD,RATIOS,CEE,E2,VASODILATATION,INFLAMMATION,LESION PROGRESSION,E2,VASODILATATION,INFLAMMATION,PLAQUE INSTABILITY,PLAQUE THROMBOSIS,机会窗假说,Windows of opportunity,激素替代疗法应用原则,The principal indication for HRT is to relieve menopause-related symptoms.,HRT should be prescribed to women with an early onset of the menopause.,HRT should be used in the smallest doses that are effective,for the shortest time necessary.,HRT must be individualized.,HRT is not recommended for the primary prevention of cardiovascular diseases and the prevention of age-related diseases.,Informing women about hormone replacement therapy:the consensus conference statement.BMC,Womens,Health.2009;9:14-18.,离开导师如何继续深入？,创新性、可行性,创新性：科学价值、创新点（阅读文献）,可行性：理论可行性、技术可行性、人员可行性、经费的可行性。,积累的过程，兴趣、韧性。,欢迎有兴趣精力的同学参于研究,广州中医药大学生理教研室基础楼,529,