基因多态性对钙离子通道阻滞剂类抗高血压药物药动学及疗效的影响

钙离子通道阻滞剂是常用的一种高血压治疗药物,其中又以二氢吡啶类钙离子通道阻滞剂为主要代表,常见的有硝苯地平、氨氯地平、非洛地平等。然而,不同的患者个体对此类抗高血压药物可产生不同的降压效果,这种差异是环境和遗传共同作用的结果。基因多态性决定了药物代谢酶、转运体以及作用受体的差异,是导致药物疗效差异的重要原因之一。综述药物代谢酶、转运体和作用受体的基因多态性对钙离子通道阻滞剂类抗高血压药物的药动学和疗效的影响。     

在中国北方汉族人群中血管紧张素转换酶基因I/D多态与G蛋白beta3亚基基因C825T多态对原发性高血压的联合作用

原发性高血压是一种复杂的多基因疾病,被认为是多个变异了的基因遗传交互以及环境因素共同作用的结果.证据表明,血管紧张素转换酶基因和G蛋白beta3亚基基因各自都是重要的原发性高血压的易感基因,并且可能存在共同的通路来导致高血压疾病的发展.为了探索这两个基因在中国北方汉族人群中是否对高血压有影响,挑选血管紧张素转换酶基因I/D多态与G蛋白beta3亚基基因C825T多态,在一个包含502个高血压病例和490个健康对照的样本中做了关联研究.连锁不平衡分析揭示,仅仅在男性中有显著性的非随机性分布,表明血管紧张素转换酶基因与G蛋白beta3亚基基因倾向在男性中造成高血压.调整了的单位点的多变量逐步回归分析展示,在男性显性模型中DD/ID对Ⅱ的比值比达到显著性水平(OR1.57;95%CI,1.09～2.27;P=0.016).在对性别进行分层后的联合分析中,在男性中经过调整后的比值比具有弱显著性水平:在血管紧张素转换酶基因的DD基因型中,TT对CC的比值比是0.11;95%CI,0.01～0.99;P=0.049;在G蛋白beta3亚基基因的CC CT基因型中,DD/ID对Ⅱ的比值比是1.52;95%CI,1.01～2.29;P=0.047.结果暗示,血管紧张素转换酶基因或附近的某个基因是具有男性性别倾向的高血压易感侯选基因,同时,在血管紧张素转换酶基因基因的D等位基因和G蛋白beta3亚基基因的825C等位基因之间,可能存在具有上位效应的基因-基因相互作用.     

L-精氨酸对大鼠肾性高血压心肌的保护作用

目的探讨L-精氨酸对大鼠肾性高血压心肌保护的作用机制。方法按体重将大鼠随机分为3组：正常对照组（5只）、高血压对照组（20只）及L-精氨酸治疗组（20只）,制作肾性高血压动物模型,L-精氨酸治疗组通过胃管灌饲给予L-精氨酸,连续给药8周后,切取各组心室肌组织,进行免疫组织化学染色,观察各组心肌组织bcl-2、bax基因的表达。利用HPIAS-2000图像分析系统测定bcl-2、bax基因在各组中表达的平均光密度和平均阳性面积率。结果bcl-2在L-Arg组的表达显著高于高血压对照组;bax在L-Arg组的表达明显低于高血压对照组。图像分析结果显示bcl-2和bax基因在两组间差异有显著性意义（P〈0.01）。结论L-精氨酸对大鼠肾性高血压导致的心肌细胞损伤具有重要的保护作用     

基因多态性与原发性高血压的相关性

高血压是一种遗传因素和环境因素相互作用所致的疾病,但高血压的病因尚不明确。已有的研究结果表明,高血压患者或潜在患者常有一种以上与血压调节相关的基因异常。目前,已有多个与高血压相关的基因位点被深入广泛研究。本文旨在就基因多态性与高血压相关性的研究进展进行综述。     

我国成功定位高血压易感基因

我国多基因疾病的研究目前已实现零的突破。由国家人类基因组南方研究中心、上海市高血压研究所、复旦大学遗传学研究所等多家单位联合组成的课题组,近日成功地定位了一处高血压易感基因的精细位点。高血压是人类心脑血管疾病中危害最大的一种多基因疾病,目前世界各国的科学家都在竞相寻找引起高血压的易感基因。我国的科研人员通过对上海地区346个原发性高血压家系的1500多名成员的基因样本,进行先进的微卫星全基因扫描、分型和连锁分析,发现在人类2号染色体2q14－q23区域存在高血压的易感基因。这一研究的相关论文已发表在美国的《高…     

肠道菌群与高血压及其危险因素研究进展及问题探讨

高血压是目前最常见的心血管疾病之一，已成为全球范围内的公共卫生问题。众所周知，维持血压稳态是一个复杂的过程，高血压是一种受多种因素影响的疾病，主要受遗传和环境因素影响。核酸测序揭示肠道菌群所包含的基因是人类基因的100多倍，这些基因产生的激素、神经递质和炎症分子可以进入宿主循环而影响宿主生理变化。目前越来越多的研究表明肠道菌群及其代谢产物能影响机体的代谢、免疫和内环境稳态等，从而在高血压发病机制中起主要作用。因此，通过调节肠道菌群及其代谢产物可作为治疗高血压的新策略。     

原发性高血压相关基因DNA甲基化的研究进展

高血压是常见的慢性疾病,也是心脑血管病最主要的风险因素。原发性高血压是由多基因和环境因素共同作用引起的复杂疾病,但具体的发病机制仍不清楚。随着研究的深入,DNA甲基化等表观遗传学因素在原发性高血压病理过程中起到的作用逐渐受到重视。本文总结了部分原发性高血压关联基因中DNA甲基化在其患病中的研究进展,阐述可受环境因素影响的DNA甲基标记与原发性高血压的关系,进一步了解高血压的发病机制。     

SLC12A3基因rs11643718位点基因多态性与EH发病的多因素分析

为探讨SLC12A3基因rs11643718位点基因多态性与原发性高血压(EH)发病的关系及对EH患者的健康教育对策,本研究选取心血管内科门诊确诊的高血压患者150例(EH组)、健康自愿者300例进行调查(对照组),采用聚合酶链反应(PCR)技术检测两组人群的SLC12A3基因rs11643718位点基因多态性,并收集两组的一般资料、生活行为方式资料,采用多因素分析EH发病的危险因素及其防治对策。研究发现EH组患者的SLC12A3基因rs11643718位点基因型与对照组比较差异无统计学意义(p0.05);EH组SLC12A3基因rs11643718位点等位基因频率A (10.57%)显著的低于对照组"16.33%",差异具有统计学意义(p0.05);采用Logistic回归分析可知,食盐量、LDL-C、TC、TG增加、SLC12A3基因rs11643718位点等位基因频率A降低是人群发生高血压的独立危险因素,差异有统计学意义(p0.05)。本研究的结果说明,高血压的发病受多种因素的影响,SLC12A3基因rs11643718位点等位基因频率A表达可以降低人群发生高血压疾病的风险。     

高血压Ⅱ期患者细胞因子诱生水平的研究

高血压是一种以平滑肌细胞增生为主要病变的疾病。近来的研究结果表明:高血压时,血管平滑肌细胞处于“合成状态”,细胞可以分裂、增殖,并有迁移性,此时血管平滑肌细胞内myc mRNA增加了14％～100％。汤健等也发现自发性高血压大鼠血管平滑肌细胞、心肌和肝脏中myc基因的转录水平明显高于wky大鼠。除此之外,sis基因表达亦高于wky大鼠,而fos基因的表达则高出wky大鼠5～8倍。由此可见,myc、fos、sis癌基因的激活可能引起平滑肌细胞增殖和肥厚,进而导致高血压发生。     

原发性高血压相关新基因的发现--D1S249位点与汉族EH相关联

原发性高血压(essential hypertension, EH)被认为是多基因、多因素相互作用引起的复杂疾病. 过去10年中, 高血压相关基因研究虽然已取得令人高兴的进展, 但究竟有多少基因参与发病, 及其之间的相互作用仍不清楚. 以北京房山区高血压群体及家系为研究对象, 应用全基因组扫描技术, 通过病例-对照相关研究和98对受累同胞对连锁分析, 筛查鉴定与汉族原发性高血压相关联的新基因位点. 病例-对照群体分析结果表明, 位于1号染色体长臂1q32区的D1S249微卫星多态性位点与汉族原发性高血压相关联,χ2 = 14.6, P = 0.002. 该位点存在12种等位基因, A9等位基因(181 bp)频率在高血压组较对照组明显升高, 两组间频率为13.6% v.s 2.7%, χ2 = 6.30, P = 0.01(OR = 4.57, 95% CI = 1.21～25.4); 98对受累同胞对等位基因共享连锁分析显示, χ2 = 3.78, P = 0.048. 上述结果提示, D1S249微卫星多态位点与北京房山区汉族原发性高血压遗传易感相关联, 致病基因可能于D1S249位点存在连锁不平衡.     

Gene therapy in cancer

Gene therapy, recently frequently investigated, is an alternative treatment method that introduces therapeutic genes into a cancer cell or tissue to cause cell death or slow down the growth of the cancer. This treatment has various strategies such as therapeutic gene activation or silencing of unwanted or defective genes; therefore a wide variety of genes and viral or nonviral vectors are being used in studies. Gene therapy strategies in cancer can be classified as inhibition of oncogene activation, activation of tumor suppressor gene, immunotherapy, suicide gene therapy and antiangiogenic gene therapy. In this review, we explain gene therapy, gene therapy strategies in cancer, approved gene medicines for cancer treatment and future of gene therapy in cancer. Today gene therapy has not yet reached the level of replacing conventional therapies. However, with a better understanding of the mechanism of cancer to determine the right treatment and target, in the future gene therapy, used as monotherapy or in combination with another existing treatment options, is likely to be used as a new medical procedure that will make cancer a controllable disease.     

Technology for gene transfer into hematopoietic stem cells (Part 2)]

A hematopoietic stem cell is considered to be one of the ideal targets for gene therapy, and there is expectation that gene therapy will be established based on the technology of hematopoietic stem cell transplantation. However, in recent clinical trials of stem cell gene therapy for monogenic diseases, significant clinical improvement has not been reported. One of the main obstacles is the low efficiency of gene transfer into hematopoietic stem cells. Many investigators have been trying to improve the transduction efficiency to the clinically applicable level. Another approach to solve this problem is to develop the method for selective expansion of transduced hematopoietic stem cells in vivo. We are currently developing novel regulatory genes (selective amplifier genes) for stem cell gene therapy.     

A microarray gene analysis of peripheral whole blood in normal adult male rats after long-term GH gene therapy

The main aims of this study were to determine the effects of GH gene abuse/misuse in normal animals and to discover genes that could be used as candidate biomarkers for the detection of GH gene therapy abuse/misuse in humans. We determined the global gene expression profile of peripheral whole blood from normal adult male rats after long-term GH gene therapy using CapitalBio 27 K Rat Genome Oligo Arrays. Sixty one genes were found to be differentially expressed in GH gene-treated rats 24 weeks after receiving GH gene therapy, at a two-fold higher or lower level compared to the empty vector group (p < 0.05). These genes were mainly associated with angiogenesis, oncogenesis, apoptosis, immune networks, signaling pathways, general metabolism, type I diabetes mellitus, carbon fixation, cell adhesion molecules, and cytokine-cytokine receptor interaction. The results imply that exogenous GH gene expression in normal subjects is likely to induce cellular changes in the metabolism, signal pathways and immunity. A real-time qRT-PCR analysis of a selection of the genes confirmed the microarray data. Eight differently expressed genes were selected as candidate biomarkers from among these 61 genes. These 8 showed five-fold higher or lower expression levels after the GH gene transduction (p < 0.05). They were then validated in real-time PCR experiments using 15 single-treated blood samples and 10 control blood samples. In summary, we detected the gene expression profiles of rat peripheral whole blood after long-term GH gene therapy and screened eight genes as candidate biomarkers based on the microarray data. This will contribute to an increased mechanistic understanding of the effects of chronic GH gene therapy abuse/misuse in normal subjects.     

Therapeutic genes for cancer gene therapy

Cancer still represents a disease of high incidence and is therefore one major target for gene therapy approaches. Gene therapy for cancer implies that ideally selective tumor cell killing or inhibition of tumor cell growth can be achieved using nucleic acids (DNA and RNA) as the therapeutic agent. Therefore, the majority of cancer gene therapy strategies introduce foreign genes into tumor cells which aim at the immunological recognition and destruction, the direct killing of the target cells or the interference with tumor growth. To achieve this goal for gene therapy of cancer, a broad variety of therapeutic genes are currently under investigation in preclinical and in clinical studies. These genes are of very different origin and of different mechanisms of action, such as human cytokine genes, genes coding for immunstimulatory molecules/antigens, genes encoding bacterial or viral prodrug-activating enzymes (suicide genes), tumor suppressor genes, or multidrug resistance genes.     

Protection of CHO cells by transfer of survivin driven by ovarian-specific promoter OSP-2

Chemotherapy is the major therapy for cancer in clinic. However, chemotherapeutic agents can harm the other tissues/organs besides cancer. Thus, there are great interests in protecting the innocents by the transfer of protective genes. There are two problems to be solved, one is the selection of protective genes and the other is the orientation of the exotic genes. Recent researches demonstrated that the principal mechanism of chemotherapeutics was through apoptosis. Hereby, introduction of anti-apoptosis genes might interrupt the processes of apoptosis to avoid side effect from chemotherapeutics. On the other hand, tissue-specific promoters, which control gene expression in a tissue-specific manner, might be an alternative tool to guarantee the location of target genes. In this research, we applied gene therapy to chemoprotection using anti-apoptosis gene survivin and ovarian-specific promoter OSP-2. The results showed that OSP-2 could specifically drive the expression of survivin in ovarian cells and survivin could protect cells via inhibiting apoptosis. This might put a light on the future of chemoprotective gene therapy.     

肿瘤基因治疗的研究进展

肿瘤是严重影响人类身体健康的重大疾病之一,肿瘤的发生发展是一个复杂的涉及到众多基因的过程,肿瘤的基因治疗也已经成为肿瘤治疗的研究热点之一。目前,肿瘤基因治疗的策略主要包括以下几个方面:基因沉默治疗、抑癌基因治疗、免疫基因治疗、自杀基因疗法、抑制肿瘤血管生成基因治疗、肿瘤多药耐药基因治疗、抗端粒酶疗法和多基因联合疗法等。我们简要地对上述策略及相关研究进展进行综述。     

米非司酮基因诱导调控系统

在基因表达和基因治疗研究中,需要目的基因在特定的时间以适当的水平实现其表达,目的基因过度表达或不适当的表达将影响实验结果,在疾病治疗中甚至会产生致命的副作用,实现对目的基因的表达时间和表达水平的精确调控是一个非常关键的问题。目前生物学家们已构建了多种新型的基因表达调控系统,其中米非司酮诱导调控系统具有诱导效率高,背景表达低,安全性高等诸多优点,是基因调控研究中的重要进展,也是目前最有应用前景的调控系统之一。本文就其结构设计和应用研究方面的进展作一简要综述。     

选择性复制型腺病毒介导的自杀基因HSV -tk 在 肿瘤基因治疗中的应用

自杀基因治疗是肿瘤基因治疗的手段之一,治疗效果与自杀基因能否被高效、选择性的导入肿瘤细胞有关。肿瘤选择性复制型腺病毒（conditionally replication adenovirus,CRADs）可以特异性的在肿瘤细胞中复制,在复制的同时所携带的治疗基因也大量表达。由CRAds介导的自杀基因,实现了对肿瘤的病毒治疗和基因治疗的结合,提高了治疗效率和使用复制型腺病毒的安全性。     

Cancer immunogene therapy: A review

Although immunotherapy has long held out promise as a specific, potent approach to cancer therapy, clinical applications have been unrewarding to date. However, advances in gene transfer technology and basic immunology have opened new avenues to stimulate antitumor immune responses including immunogene therapy. Many different approaches to immunogene therapy have been identified. These include transferring genes encoding proinflammatory proteins to tumor cells, suppressing immunosuppressive gene expression, and transferring proinflammatory genes and/or tumor antigen genes to professional antigen-presenting cells. In some cases, genes are transferred to tumor or antigen-presenting cells in situ. In others, gene transfer is performed ex vivo as part of preparing an anticancer vaccine. We discuss the underlying approach, relative success, and clinical application of various cancer immunogene therapy strategies, paying particular attention to immunogene therapy vaccines. Large numbers of preclinical studies have been reported, but only scattered clinical trial results have appeared in the literature. Although very successful preclinically, the ideal cancer immunogene therapy approach remains to be determined and will likely vary with tumor type. Clinical impact may be improved in the future as treatment protocols are refined.     

Prostate cancer gene therapy-what have we learned and where are we going?

With recent advances in genetic engineering, tumor biology, and immunology, gene therapy has been recognized as a promising new treatment option for various cancers, including prostate cancer. Several clinical trials of prostate cancer gene therapy, using therapeutic genes which include suicide genes, immunomodulatory genes, tumor suppressor genes, and anti-oncogenes, are under way and preliminary reports have emerged. Although gene therapy for prostate cancer is still at an early stage and requires additional technological breakthroughs, new insights obtained from recent clinical trials indicate a promising potential for prostate cancer gene therapy. In this report, general concepts, current progress, and future prospects in prostate cancer gene therapy are summarized.