生物技术药物之重组多肽蛋白质类激素药物.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,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,*,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,*,生物技术药物之重组多肽蛋白质类激素药物,血细胞生长因子类药物,对造血有调控作用的细胞因子，造血细胞因子。,糖蛋白，分子量较小，旁分泌途径，作用浓度低，调控多样化，多能，与受体作用，具增殖、分化、成熟和修饰功能。,种类,白介素家族，集落刺激因子，促红细胞生成素，干细胞因子，促血小板生成素（正因子）,干扰素（负因子）,促血小板生成素,巨核细胞生成素,Thrombopoietin TPO,来源于肝，肾和骨骼肌细胞。,353,个氨基酸组成，糖蛋白，两个二硫键,刺激巨核细胞生长及分化的内源性细胞因子，对巨核细胞生成的各阶段均有刺激作用，包括前体细胞的增殖和多倍体巨核细胞的发育及成熟，从而升高血小板数目。,用于化疗或放疗引起的血小板减少症,副作用小,利用基因重组技术由中国仓鼠卵巢细胞表达，经提纯制成的全长糖基化血小板生成素，与内源性血小板生成素具有相似的升高血小板的药理作用,Thrombopoietin is a,glycoprotein,hormone produced mainly by the liver and the kidney that regulates the production of platelets by the bone marrow.It stimulates the,production and differentiation of megakaryocytes,the bone marrow cells that fragment into large numbers of platelets.,Its negative feedback is different from most hormones in endocrinology:the effector regulates the hormone directly.,Thrombopoietin is bound to the surface of platelets by the mpl receptor,(CD 110)and destroyed,thereby reducing megakaryocyte exposure to the hormone.Therefore,the rising and dropping platelet concentrations regulate the thrombopoietin levels.,Low platelets,lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells;leading to differentiation into megakaryocytes and further maturation of these cells.,On the contrary,high platelet,concentrations lead to the reversal of these physiologic mechanisms.,细胞集落刺激因子类药物,集落刺激因子,(colony stimulating factor),在进行造血细胞的体外研究中，发现一些细胞因子可刺激不同的造血干细胞在半固体培养基中形成细胞集落，这类因子被命名为集落刺激因子（,CSF,）。,粒细胞,CSF,（,G-CSF,），巨噬细胞,CSF,（,M-CSF,），粒细胞和巨噬细胞,CSF,（,GM-CSF,）和多潜能集落刺激因子,(multi-CSF,又称,IL-3),，都有刺激造血细胞增殖作用。,酸性糖蛋白，较小分子量,作用细胞：,粒细胞集落刺激因子,粒细胞集落刺激因子,Granulocyte colony-stimulating factor,，,G-CSF,由活化的单核和巨噬细胞产生；成纤维细胞，内皮细胞等也可在激活后产生,G-CSF,糖蛋白，,174/177,个氨基酸，两对二硫键,作用于中性粒细胞系造血细胞的增殖、分化和活化。,The G-CSF-R is a transmembrane receptor that is responsible for signal transduction.GCSF-R ligand-binding is associated with dimerization of the receptor and signal transduction through proteins including Jak,Lyn,STAT,and Erk1/2.,G-CSF,或,/,和,SCF,协同可促进造血多能干细胞的增殖干细胞母细胞集落形成,临床用于化疗辅助治疗,(,减少骨髓抑制，促进中性粒细胞恢复,),，慢性白血病减少症，骨髓移植等。,不良反应 骨痛，流感样症候群等,巨噬细胞集落刺激因子,macrophage colony-stimulating factor,，,M-CSF,M-CSF,为链间二硫键连接而成的二聚体糖蛋白,主要存在于骨髓腔内,对单核细胞的增殖、分化及维持其活性有重要作用。,其受体为,c-Fms(,是酪氨酸激酶受体家族成员之一,),。,c-Fms,的胞外区含有,5,个,Ig,样结构域,胞内区具有酪氨酸激酶活性,是具有单一高亲和力受体分子。,M-CSF,与,c-Fms Ig,样结构域的,D1,、,D2,和,D3,结合,引起,D4,构象变化、受体二聚化而导致胞内区酪氨酸激酶的活化。它的功能涉及,STATs,、,JAK,、,Ras,、,Raf-1,、,MEK,、,MAPK,以及,PI-3K,、,PKC,等。,多种细胞均可分泌：成纤维细胞等,The chain is involved in signal transduction.,来源于肝，肾和骨骼肌细胞。,EpoR is a protein that in humans is encoded by the EPOR gene.,糖蛋白，分子量较小，旁分泌途径，作用浓度低，调控多样化，多能，与受体作用，具增殖、分化、成熟和修饰功能。,不良反应 骨痛，流感样症候群等,Upon dimerisation of the and subunits the subunit becomes phosphorylated on tyrosine residues by members of the Janus kinase(JAK)family.,增强成熟造血细胞的活性,不良反应：发热，头痛等,Low platelets lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells;leading to differentiation into megakaryocytes and further maturation of these cells.,酸性糖蛋白，较小分子量,炎症反应中的介质，可能与某些癌症，全身性红斑狼疮等,152个氨基酸，成熟时切除19个氨基酸，二硫键，糖蛋白（糖基化不影响活性）,促进单核,-,巨噬细胞包括破骨细胞在内的存活、增殖和分化,炎症反应中的介质，可能与某些癌症，全身性红斑狼疮等,化疗辅助治疗，真菌感染，高血脂,不良反应：皮疹，肝脏损害等,粒细胞和巨噬细胞,CSF,（,GM-CSF,）,多种细胞可产生,Granulocyte-macrophage colony-stimulating factor(GM-CSF)is a protein secreted by,macrophages,T cells,mast cells,NK cells,endothelial cells and fibroblasts,.,其中,T,细胞和巨噬细胞在免疫应答或炎症介质刺激过程中直接产生,144,个氨基酸，,17,个氨基酸引导序列，二个二硫键,The granulocyte macrophage colony-stimulating factor,receptor,is a heterodimer composed of at least,two different subunits,;an chain,and a chain which is also present in the receptors for IL-3 and IL-5.The,subunit contains a binding site,for granulocyte macrophage colony-stimulating factor.The,chain is involved in signal transduction,.Association of the and subunits results in receptor activation,Upon dimerisation of the and subunits the subunit becomes phosphorylated on tyrosine residues by members of the,Janus kinase(JAK)family,.This leads to association with a,Shc adaptor protein,.Then Shc interacts with,GRB2/SoS complex,which results in activation of more,downstream molecules,in the pathway.,促进造血祖细胞增殖，分化（中性粒细胞和巨噬细胞）；增强成熟造血细胞的活性,肿瘤放化疗辅助治疗，骨髓移植，骨髓增生异常综合征,/,再生障碍性贫血，艾滋病,不良反应：发热，骨痛等,多潜能细胞集落刺激因子,(IL-3),Mulit-CSF,由活化,T,细胞产生,152,个氨基酸，成熟时切除,19,个氨基酸，二硫键，糖蛋白（糖基化不影响活性）,生物学功能：诱导表达,20a-SDH,（,T,细胞成熟标记之一），刺激肥大细胞增殖，刺激红细胞生长素诱导的红系细胞集落形成，刺激淋巴细胞增殖和分化，增加,NK,细胞细胞毒性作用,临床 免疫力低下，再生障碍性贫血,不良反应：发热，头痛等,IL-3 stimulates the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells or,with the addition of IL-7,into lymphoid progenitor cells.Additionally,IL-3 stimulates proliferation of all cells in the myeloid lineage(granulocytes,monocytes,and dendritic cells),in conjunction with other cytokines,e.g.,Erythropoietin(EPO),Granulocyte macrophage colony-stimulating factor(GM-CSF),and IL-6.,It is secreted by basophils and activated T cells to support growth and differentiation of T cells from the bone marrow in an immune response,.Activated T cells can either induce their own proliferation and differentiation(autocrine signalling),or that of other T cells(paracrine signalling)-both involve IL-2 binding to the IL-2 receptor on T cells(upregulated upon cell activation,under the induction of macrophage-secreted IL-1).The human IL-3 gene encodes a protein,152 amino acids,long,and the naturally occurring IL-3 is glycosylated.The human IL-3 gene is located on chromosome 5,only 9 kilobases from the GM-CSF gene,and its function is quite similar to GM-CSF.,The receptor is composed of a ligand specific,alpha subunit,and a,signal transducing beta subunit,shared by the receptors for interleukin 3(IL3),colony stimulating factor 2(CSF2/GM-CSF),and interleukin 5(IL5).The binding of this protein to IL3 depends on the beta subunit.The beta subunit is activated by the ligand binding,and is required for the biological activities of IL3.,促红细胞生成素,Erytropoietin,，,EPO,肾脏，间质细胞（组织缺氧诱导产生,EPO,）,刺激和调节红细胞的生成：促进红系细胞的生长，分化和增殖，促进红系池的扩大；促进红细胞成熟；抗氧化作用,临床应用：,肾功能衰竭引起的贫血,癌性贫血,结缔组织病贫血,骨髓增生异常综合症贫血,不良反应：,肾性,/,非肾性贫血,不良反应 骨痛，流感样症候群等,炎症反应中的介质，可能与某些癌症，全身性红斑狼疮等,It stimulates the production and differentiation of megakaryocytes,the bone marrow cells that fragment into large numbers of platelets.,炎症反应中的介质，可能与某些癌症，全身性红斑狼疮等,来源于肝，肾和骨骼肌细胞。,酸性糖蛋白，较小分子量,353个氨基酸组成，糖蛋白，两个二硫键,Additionally,IL-3 stimulates proliferation of all cells in the myeloid lineage(granulocytes,monocytes,and dendritic cells),in conjunction with other cytokines,e.,生物学功能：诱导表达20a-SDH（T细胞成熟标记之一），刺激肥大细胞增殖，刺激红细胞生长素诱导的红系细胞集落形成，刺激淋巴细胞增殖和分化，增加NK细胞细胞毒性作用,152个氨基酸，成熟时切除19个氨基酸，二硫键，糖蛋白（糖基化不影响活性）,集落刺激因子(colony stimulating factor),Low platelets lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells;leading to differentiation into megakaryocytes and further maturation of these cells.,The beta subunit is activated by the ligand binding,and is required for the biological activities of IL3.,不良反应：发热，头痛等,The granulocyte macrophage colony-stimulating factor receptor is a heterodimer composed of at least two different subunits;an chain,and a chain which is also present in the receptors for IL-3 and IL-5.,临床 免疫力低下，再生障碍性贫血,EpoR is a 59 kDa peptide and is a member of the cytokine receptor family.,EpoR is a protein that in humans is encoded by the EPOR gene.EpoR is a 59 kDa peptide and is a member of the cytokine receptor family.,EpoR pre-exists as dimers which upon binding of a 34 kDa ligand erythropoietin(Epo),changes its homodimerized state.,These conformational changes result in the autophosphorylation of,Jak2,kinases that are pre-associated with the receptor(i.e.,EpoR does not possess intrinsic kinase activity and depends on Jak2 activity).,谢谢观看,谢谢观看,