生化课件sensory immune sys‹#›单击此处编辑母

1、1Responding to Environmental Changes郑利民郑利民 2012 广州广州 E-mail: 2别挤啦！再挤就别挤啦！再挤就!Cancer: An uncontrolled cell growth that breach homeostasis456细胞存活细胞存活细胞凋亡细胞凋亡The balance between pro- and anti-apoptotic genes/signals determine the cell fate细胞接受到细胞接受到“死亡信号死亡信号”，不一定就会死亡，不一定就会死亡若同时也接受到若同时也接受到“生存信号生存信号”，就可继

2、续存活，就可继续存活7cell cycle: A process of cellular reproduction 8Four phases: G1, S, G2, MGap (G1 and G2) phases: Respond to proliferative and anti-proliferative signals, synthesize RNA and proteinSynthetic (S) phase: Replication of the chromosomesMitotic (M) phase: segregation of chromosomes and other ce

3、ll constituents into two daughter cells9Cell cycle transits orderly and irreversibly10Cell cycle transits orderly and irreversiblynThe completion of one phase is required for the beginning of the next.nPeriodic activation of specific cyclin-Cdk complexes nA cycle of protein destruction eliminates pr

4、oteins used in the preceding phase as well as proteins that would inhibit progression into the next phase.11Cyclin-dependent kinases (Cdks)nCdks drive cell cycle progression by phosphorylating a group of substrates- Cdks present a unique pattern of activity in each phase of the cell cycleCdk1 (Cdc2)

5、Cdk2Cdk3Cdk4 Cdk5Cdk6Cdk7G1G2, MLate G1, SG1, S, G2, M12Regulation of Cdks activity Cyclin: Activating subunit. Cyclins were named because of their cyclic expression during the cell cycleMitogen Stimulation13Four mechanisms regulate CDK activity: 1 phosphorylation or dephosphorylation, 2 controlled

6、degradation of cyclin subunit, 3 periodic synthesis of CDKs and cyclins, 4 action of specific CDK inhibiting proteins.14Growth controlling signals are conveyed by stimulatory or inhibitory pathways1617 Olfaction - smell Gustation - taste Vision - see, view Hearing - listen Touching change by skin Al

7、l based on Signal-transduction pathways activated by the environments18Detection of different chemicals in airLocation: Main Olfactory (Nasal) EpitheliumShape of molecule is responsible for their smellsFeatures: specific, detect a vast array of odorantsOdorants are decoded by a combinatorial mechani

8、sm19 Specific region that detect odorants纤毛纤毛20Molecular events of olfaction These interactions occur in the cilia of olfactory receptors (OR)OR family A Seven TMR1000 gene in mouse, 500 in human (most of them are pseudogenes) 21Odorant Receptor (OR)Blue: strongly conservedRed: highly variablegreen

9、cylinders: 7 presumed TM helices The highly variable central region, (h4 & 5), is site of odorant binding, differs in OR that bind distinct odorant molecules. Each olf. neuron expresses only a single OR gene among hundreds, determined at random22Chewing gums绿薄荷绿薄荷香菜香菜The shape of molecule is cru

10、cial (stereo-specific)2324Patterns of OR activationTest responses of different OR. Colored box: OR (top) responded to compound (left) Darker colors: OR activated at a lower concentration of odorantOne Odorant activates several OR;One OR is activated by 1 odorantA small array of OR distinguish a vast

11、 number of odorants 25Taste-sensitive areas of tongueFive primary tastes: Bitter Sweet Salt Sour Umami (Glutamate, delicious)2. TasteBack26Bitter receptorGustducinBitter & sweet: experienced via 7-TM receptorsacting through a special G protein, Gustducin27Salty & sour: directly via membrane

12、ion channels Salt: detected by passage though sodium channelsSour: results from the effects of H+ on various channels.Umami: by a modified form of one brain receptor that responds to glutamate as a neurotransmitter2829Differing gene expres. & connec. patterns in OR & TROR: each neuron expres

13、ses a single OR, neurons expressing same OR converge to specific sites in brain.BR（苦味）（苦味）each neuron expresses many BR genes, so the identity of the tastant is lost in transmission.30J. Clin. Invest. 2005；115:2965-7Taste bud and structure of TR for fat CD36 on the apical surface of taste cells啮齿动物偏

14、好油味，特别是对啮齿动物偏好油味，特别是对长链脂肪酸长链脂肪酸 (植物油等）。舌头植物油等）。舌头上的味蕾细胞的顶面存在上的味蕾细胞的顶面存在CD36，可感受到饮食中的油味。该基可感受到饮食中的油味。该基因敲除后的小鼠不再对含油食因敲除后的小鼠不再对含油食物表现出偏好。物表现出偏好。 油在鼠的口中就会引起胆汁和油在鼠的口中就会引起胆汁和胰液分泌，以助消化；该过程胰液分泌，以助消化；该过程需要需要CD36参与。参与。 若能理解为什若能理解为什么油脂食物如此美味，肯定有么油脂食物如此美味，肯定有助于我们另寻妙方来攻克肥胖。助于我们另寻妙方来攻克肥胖。313. Visionnbased on the

15、 absorption of light by photoreceptor cells: cones, respond to bright lights and colors, rods, only to dim light.nOnly sensitive to visible light (330-850nm)圆锥圆锥32a 7TM receptor, complex of protein opsin 视蛋白视蛋白 and chromophore 11-cis-retinal. Absorption of light changes structure into all-trans-reti

16、nal.33Activation of rhodopsin by light.Notice the structural change of retinal顺式顺式3435Absorption of light changes structure into all-trans-retinal, setting in motion a signaling pathway that leads to breakdown of cGMP, to hyperpolarization, then nerve impulse.36Molecular consequences of photon absor

17、ption by rhodopsin in the rod outer segment37Mediated by 3 distinct 7-TM photoreceptors that employ 11-cis-retinal as a chromophore; absorb light in blue, green, & red spectrumAbsorption spectra of the cone visual pigment responsible for color vision. Blue (426), green (530) and red (560)3839Hai

18、r cellsHair bundleTip links40Hair bundle tip toward the tallest part, the tip link pulls on and opens an ion channelMovement in the opposite direction relaxes the tension in the tip link, close any open channels.41nTwo key components: pressure & temperature nNociceptors: specialized neurons tran

19、smit signals, interpreted by brain as painnVR1(the capsaicin receptor), functions as a cation channel that initiates a nerve impulsen“pain” vs “spicy taste”Capsaicin and its receptornoci: 伤害伤害capsaicin：辣椒素：辣椒素42Magnetotactic: in directions dictated by Earths magnetic fieldAbility to respond to chemi

20、cal signals called pheromones, released by other personsSense of time, manifested in our circadian rhythms of activity and restfulness；influenced by daily changes in light Magnetotactic bacteriumphero: 信息信息circadian：生理节奏：生理节奏43抗利尿激素抗利尿激素44Summary for Sensory Transduction in Vision,Olfaction, and Gus

21、tationIn vertebrates, they employ serpentine receptors, act through heterotrimeric G proteins to change the Vm of the sensory neuronThere is a high degree of conservation of signaling proteins and transduction mechanisms across species信号转导异常的原因和机制信号转导异常的原因和机制一、信号转导异常一、信号转导异常1. 1.生物学因素：生物学因素： 干扰细胞内信号

22、转导通路干扰细胞内信号转导通路: :如霍乱毒素如霍乱毒素2. 2. 理化因素：理化因素：电离辐射或机械刺影响信号转导成分而致电离辐射或机械刺影响信号转导成分而致癌癌3.3.遗传因素：信号蛋白数量遗传因素：信号蛋白数量/ /功能改变（功能改变（突变）突变）4.4.免疫学因素：刺激型和阻断型抗受体抗免疫学因素：刺激型和阻断型抗受体抗体体5.5.内环境因素内环境因素46二、信号转导异常的发生环节二、信号转导异常的发生环节V2RGsACcAMPATPPKAADHH2OH2O配体、受体或受体后信号通路的任何一个环节配体、受体或受体后信号通路的任何一个环节出现障碍都会影响到最终效应，使细胞增殖、出现障碍都

23、会影响到最终效应，使细胞增殖、分化、凋亡、代谢或功能失常，并导致疾病。分化、凋亡、代谢或功能失常，并导致疾病。以尿崩症为例以尿崩症为例ADHADH作用的三个环节异常均可导致尿崩症：作用的三个环节异常均可导致尿崩症： ADH ADH分泌减少分泌减少 中枢性尿崩症中枢性尿崩症 ADH-V2 ADH-V2受体变异受体变异 肾小管上皮细胞水通道蛋白（肾小管上皮细胞水通道蛋白（AQP2AQP2）异常）异常集合管上皮细胞对集合管上皮细胞对ADHADH的反应性降低的反应性降低家族性尿崩症家族性尿崩症不同受体介导的信号转导通路存在不同受体介导的信号转导通路存在cross-talk 并非所有的信号转导蛋白异常都

24、能导致疾病并非所有的信号转导蛋白异常都能导致疾病48细胞信号转导异常与疾病细胞信号转导异常与疾病 受体、信号转导障碍与疾病受体、信号转导障碍与疾病 受体数量减少受体数量减少 受体亲和力降低受体亲和力降低 受体阻断型抗体的作用受体阻断型抗体的作用 协同因子或辅助因子缺陷协同因子或辅助因子缺陷 受体功能缺陷受体功能缺陷 受体后信号转导蛋白缺陷受体后信号转导蛋白缺陷特定信号转导过程减弱或中断特定信号转导过程减弱或中断激素抵抗征激素抵抗征49雄激素受体缺陷与雄激素抵抗征雄激素受体缺陷与雄激素抵抗征原因和机制：原因和机制：AR减少或失活突变减少或失活突变男性假两性畸形男性假两性畸形特发性无精症症特发性无

25、精症症延髓脊髓性肌萎缩延髓脊髓性肌萎缩50胰岛素受体与胰岛素抵抗性糖尿病胰岛素受体与胰岛素抵抗性糖尿病1. 1.遗传性胰岛素受体异常，包括遗传性胰岛素受体异常，包括2.2.受体的合成减少受体的合成减少3.3.与配体的亲和力降低，如与配体的亲和力降低，如Arg735Arg735突变为突变为SerSer4.4.TPKTPK活性降低，如活性降低，如Gly1008 Gly1008 突变等突变等5.5. 2.2.自身免疫性胰岛素受体异常自身免疫性胰岛素受体异常6.6.血液中存在抗胰岛素受体的抗体血液中存在抗胰岛素受体的抗体51二、受体、信号转导过度激活与疾病二、受体、信号转导过度激活与疾病 某些信号转导

26、蛋白过度表达某些信号转导蛋白过度表达 某些信号转导蛋白组成型激活突变某些信号转导蛋白组成型激活突变 刺激型抗受体抗体刺激型抗受体抗体生长激素（生长激素（GHGH）分泌过多的垂体腺瘤中，）分泌过多的垂体腺瘤中，30%30%是由于编码是由于编码GsGs的基因突变所致，从而抑制了的基因突变所致，从而抑制了GTPGTP酶活性，使酶活性，使GsGs处于持续激活状态，处于持续激活状态，cAMPcAMP含含量增多，垂体细胞生长和分泌功能活跃。量增多，垂体细胞生长和分泌功能活跃。通路过度激活通路过度激活如肢端肥大症和巨人症如肢端肥大症和巨人症52霍乱毒素选择性的催化霍乱毒素选择性的催化GsGs亚基上的亚基上的

27、Arg201Arg201核核糖化，使糖化，使GTPGTP酶活性丧失，不能将酶活性丧失，不能将GTPGTP水解成水解成GDPGDP，从而使从而使GsGs处于不可逆激活状态处于不可逆激活状态, ,不断刺激不断刺激ACAC生成生成cAMP,cAMP,胞浆中的胞浆中的cAMPcAMP含量可增含量可增加至正常的加至正常的100100倍以上，倍以上，导致小肠上皮细胞膜蛋白构型改变，大量导致小肠上皮细胞膜蛋白构型改变，大量Cl-Cl-和和水分子持续转运入肠腔，引起严重腹泻和脱水。水分子持续转运入肠腔，引起严重腹泻和脱水。53肠肠 腔腔GsCT霍乱霍乱 (Cholera)ACcAMP Cl-H2ONa+CT：

28、Cholera Toxin54三、多环节信号转导异常与疾病三、多环节信号转导异常与疾病: : 肿瘤肿瘤1. 促细胞增殖的信号转导过强促细胞增殖的信号转导过强 1). 生长因子产生增多生长因子产生增多 2). 受体：生长因子受体表达异常增多或受体：生长因子受体表达异常增多或/和突变和突变激活激活 3). 细胞内信号转导蛋白的改变细胞内信号转导蛋白的改变, 如如Ras突变突变细胞周期失控：细胞周期失控：肿瘤发生的必经步骤肿瘤发生的必经步骤破坏其调控机制：破坏其调控机制：形成肿瘤的先决条件形成肿瘤的先决条件细胞周期及其调控机制？细胞周期及其调控机制？2. 2. 抑制细胞增殖的信号转导过弱抑制细胞增殖

29、的信号转导过弱生长抑制因子受体减少、丧失生长抑制因子受体减少、丧失受体后信号转导通路异常受体后信号转导通路异常细胞的生长负调控机制减弱或丧失细胞的生长负调控机制减弱或丧失56Growth controlling signals are conveyed by stimulatory or inhibitory pathways5758Oncogene-encoded defective EGF receptor59GEF：Guanine nucleotide Exchange FactorGAP：GTPase Activating Protein Activation of Ras prote

30、in60GEF：Guanine nucleotide Exchange FactorGAP：GTPase Activating Protein Mutation of Ras constitutive activation62Oncogenes, Tumor Suppressor Genes (TSGs), and Programmed Cell Death Oncogenes: encode defective signaling proteins ( e.g., growth factors, receptors, G proteins, protein kinases, or trans

31、cription regulators), continually giving the signal for cell division; TSG: encode regulatory proteins; normally inhibit cell division; mutations in these genes are genetically recessive Cancer: the result of an accumulation of mutations in oncogenes and TSGs.To be, or not to be, that is a question!

32、Apoptosis is a tightly regulated process.Apoptosis is a tightly regulated process.1. The shift of balance between death & survival1. The shift of balance between death & survival signals determined the cell fate ( signals determined the cell fate (命运）命运）2. Usually required a number of events

33、 (or genes)2. Usually required a number of events (or genes) to control apoptosis to control apoptosisE.g., activation of one oncogenes induce apoptosisE.g., activation of one oncogenes induce apoptosisin most cases, inhibit apoptosis only with the in most cases, inhibit apoptosis only with the supp

34、ort from other signals.support from other signals. (Together we stand, separate we died) (Together we stand, separate we died) 65肿瘤形成必须是在单个细胞中发生多重遗传突变肿瘤形成必须是在单个细胞中发生多重遗传突变单个癌基因激活和抑癌基因失活不足以引起肿瘤单个癌基因激活和抑癌基因失活不足以引起肿瘤细胞的显著扩增，细胞的显著扩增，因为细胞对凋亡的易感性也同时增加；凋亡抑制因为细胞对凋亡的易感性也同时增加；凋亡抑制是肿瘤细胞能够生长到足以威胁宿主所必须的；是肿瘤细胞能够生

35、长到足以威胁宿主所必须的；例如：例如：Rb的失活仅会促进的失活仅会促进p53依赖的凋亡，但不会引起依赖的凋亡，但不会引起肿瘤，除非细胞的凋亡过程被抑制；肿瘤，除非细胞的凋亡过程被抑制；67 细胞信号转导调控与疾病防治细胞信号转导调控与疾病防治Regulation of cellular signals in prevention & treatment of diseases以信号转导蛋白为靶分子对疾病进行防治以信号转导蛋白为靶分子对疾病进行防治STI571 as a paradigm (范例）范例）for cancer therapy In 1960, described the p

36、resence of a consistent In 1960, described the presence of a consistent chromosomal abnormality in CMLchromosomal abnormality in CML（一种白血病（一种白血病) )，so-called Philadelphia chromosome (Ph)so-called Philadelphia chromosome (Ph) A reciprocal translocation between the long arms A reciprocal translocation

37、 between the long arms of chromosomes 9 and 22, t(9:22)(q34;q11),of chromosomes 9 and 22, t(9:22)(q34;q11), The molecular consequence of this event is the The molecular consequence of this event is the generation of a chimeric bcr-abl gene (22:9)generation of a chimeric bcr-abl gene (22:9)The tyrosi

38、ne kinase activity of Bcr-Abl stimulates The tyrosine kinase activity of Bcr-Abl stimulates a variety of signaling pathways, leading to a variety of signaling pathways, leading to alterations in survival properties of cellsalterations in survival properties of cells“Rational” Approach: bcr-abl direc

39、ted agentsOHOHNHCHOOHOHNHOOHCO2HHOHOOHOHOHOHNHCO2MeHNCNNHNCNNH2NNNNHNHONNMeMeerbstatinlavendustinpiceatannolAG957AG1112CGP 57148B = STI571Naturalproductempiric lead1st gen.synthetic2nd gen.synthetic;in clinicbcrSH2SH2V SH2/SH3 kinaseNTDNAActinbcrAblTyrosine kinase Ras pathwayJAK-STATpathwayPI3K pathwayFAKIntegrinActinPaxillinProliferationTransformationAdhesionGlivecNEJM 344: 1031, 2001Efficacy And Safety Of A Specific Inhibitor