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1、Disorders associated with G protein-coupled receptors-Kaposis sarcoma(卡波济肉瘤),谢喜秀 1040800114,有关卡波济肉瘤基本常识有关卡波济肉瘤的细胞学机理卡波济肉瘤的治疗,卡波济肉瘤,一种免疫缺陷的机会性肿瘤，一种皮肤的多发性血管性肉瘤，也称为“特发性多发性出血性肉瘤”艾滋病病人独具的一种恶性肿瘤，它很少在非艾滋病病人身上发生。是艾滋病病人直接死亡的原因之一，也是我国艾滋病诊断标准的一项依据奥地利皮肤病专家Kaposi（卡波济）1872年报道,临床特征,多见于躯干、四肢，也可见于面部、颈部、胸部、腹部、皮肤的多发性红
2、斑或紫色的斑块损害，为稍微隆起的硬结，压之无疼痛，不褪色；也可见于口腔黏膜及上消化道黏膜或淋巴结周围。以后累及肝、脾、胃、肠管、肺、脑、胰腺、膀胱、睾丸、前列腺（男性）、子宫、卵巢（女性）。,临床上至少可分为四型 经典型或欧洲型 非洲型 爱滋病型 移植物有关的卡波济肉瘤,经典型或欧洲型,较稀少,见于东欧,意大利和俄罗斯 病因：未明。可能与一种不明原因的感染因子有关系,非洲型（地方性Kaposi肉瘤）,主要侵犯年轻人，男女比例为13-17：1，以类似于经典Kaposi肉瘤的表面良性结节为特征。常常在5-8年内死亡，小孩可发生淋巴结病型。,爱滋病型(AIDS相关Kaposi肉瘤),流行病学：大多数
3、此类病人是男同性恋，男女比例为106：1(why？)，HIV阳性患者发展成Kaposi肉瘤的总危险率是正常人的20，000倍。平均生存时间为17月。症状与体征：多中心、对称性疾病。斑疹、斑片、丘疹或结节可发生在皮肤或黏膜的任何位置，尤其是口腔、鼻、耳后、躯干、阴茎、腿与足。淋巴结病很常见，常有疼痛性溃疡、肢体湿疹。内脏常见有胃肠道与肺的受累，任何脏器均可受累。,移植物有关的卡波济肉瘤(免役抑制型),常发生在免役抑制的器官移植患者，年龄约20-60岁，病程可慢可快，由于免疫抑制药物的不连续应用经常发生复发。,Kaposis sarcoma-associated herpesvirus（人疱疹病毒
4、8型）,In 1994,the Kaposis sarcoma-associated herpesvirus(KSHV/HHV-8)was identified as the etiologic agent（致病的相关因子）of Kaposis sarcoma(KS).which gene contributes to the initiation of KS？,latent genes：blue lytic genes：red,Latent genes are expressed in almost all spindle cells in late KS lesions Lytic gen
5、es are expressed during the phase of the viral life cycle when viral progeny are produced.these viral genes are expressed in cells ultimately destined to die(lyse),KSHV vGPCR responsible for the initiation of KS,evidence when a KS model in which endothelial-specific retroviral transduction was used,
6、vGPCR produced vascular tumors in mice two transgenic animals that express vGPCR under either a ubiquitous(SV40)promoter or a T cell-specific promoter only manifest vascular tumors,HHV-8的ORE74可编码一种G蛋白相连的受体，它以一种组成型（非拮抗剂依赖）方式，刺激与细胞增殖相联的信号传导途径，导致细胞转化和肿瘤发生，并通过血管内皮生长因子、血管生成因子、锥体细胞生长因子介导，诱导血管生成。这种受体是一种可利用
7、细胞传导途径，诱导细胞转化的病毒癌基因及介导KSHV致瘤中心血管生成的激活剂。,信号传导途径,hHV-8的ORF74,G蛋白相连的受体,细胞增殖相联的信号传导途径,细胞转化和肿瘤发生,刺激,编码,Aborted lytic cycle progression,HIV-1 Tat.inflammation,细胞内信号传导因子,血管内皮生长因子,血管生成因子,The KSHV vGPCR is a member of the family of CXC chemokine G-protein-linked receptors.this receptor exhibits ligand-indepe
8、ndent activities.activation of the serine-threonine kinase Akt by vGPCR may represent a critical intracellular pathway in the blockade of cell death,vGPCR induces the secretion of angiogenic growth factors from expressing cells,including VEGF,IL-8,and Gro-suggesting that vGPCR may serve a role both
9、in direct cell transformation and indirect(paracrine)cell transformation,Mechanisms control vGPCR,1)vGPCR is transcribed within the 3 end of a bicistronic mRNA,thus restricting its expression 2)Host cytokines(e.g.,SDF-1,IP-10)act as antagonists to vGPCR signaling,3)KSHV itself encodes a lytic gene,v
10、MIP2,whose protein product acts as an antagonist to vGPCR signaling 4)As mentioned above,as a lytic gene,vGPCR is expressed in cells ultimately destined to die.,Proliferative signals initiated by vGPCR prolong lytic cell survival to ensure efficient viral replication.proangiogenic growth factors sec
11、reted by vGPCR-expressing cells recruit neighboring endothelial cells that are then infected by the newly formed progeny virion.,How can vGPCR be responsible for the initiation of KS tumors if its expression and signaling are so tightly controlled?,under special circumstances(e.g.,HIV co-infection,i
12、nflammation,aborted lytic cycle progression),dysregulation of the normal viral program may result in nonlytic expression and enhanced signaling of vGPCR,ultimately manifesting as KS.,1)HIV Tat increases expression of KSHV lytic genes,including vGPCR,whose expression is significantly enhanced in aggr
13、essive AIDS-KS as compared with the more benign classical KS lesions 2)Several inflammatory cytokines released by HIV infected cells can increase vGPCR signaling,The critical role for these locally released inflammatory cytokines for vGPCR oncogenesis was recently confirmed by a transgenic animal en
14、coding a mutant vGPCR lacking a ligand binding domain that failed to manifest tumors despite its constitutive activity,KS治疗,（1）联合治疗 长春花碱（Vinblastine）对AIDS的KS有明显疗效，开始剂量4mg，生理盐水或5%葡萄糖20-30ml静脉注射，在维持白细胞在2.5-3109/L的情况下，渐增至每次9mg，每周一次，6-8周。春新碱（Vincristine）与长春花硷相似，对AIDS的KS有一定疗效，次，用生理盐水20-30ml静脉注射，每周一次。,足叶乙甙（etoposide vepesid）是治疗AIDS的有效药物。博来霉素，阿霉素。（2）放射疗法，可缓解症状，有效剂量1800-3000rad。（3）局部液氮冷冻（4）免疫调节剂：干扰素、异丙肌苷、胸腺素、白细胞介素等（5）vGPCR 的抗体药物,thank you,
