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1、细胞自噬与疾病（Autophagy in the Pathigenesis if Disease）,系统生物学,细胞生物学,分子生物学,系统生物学,细胞生物学,分子生物学,细胞生物学,细胞增殖细胞分化细胞死亡：形式有几种？,细胞死亡的分类,非程序性细胞死亡：Necrosis 程序性细胞死亡基于机制的分类：Apoptosis（已学）自噬性程序性细胞死亡（这次课的重点细胞自嗜）Paraptosis：形态学特征细胞浆空泡化，线粒体和内质网肿胀，但没有核固缩现象。现在Paraptosis的文献报道比较少，其机制有待于进一步深入研究。细胞有丝分裂灾难：DNA发生损害时，细胞无法进行完全的分裂从而导致四倍
2、体或多倍体的现象。胀亡(Oncosis)：特征细胞肿胀，体积增大，胞浆空泡化，肿胀波及细胞核、内质网、线粒体等胞内结构，胞膜起泡，细胞膜完整性破坏，周围有明显炎症反应。发生的机制研究尚少，有研究者认为胀亡只是坏死前的一个被动性死亡阶段，但是近年来的研究更倾向于胀亡是一个程序性的死亡方式,细胞自嗜（Autophagy）,1962年Ashford等在胰高血糖素处理的小鼠肝细胞中观察到autophagy1963年,De Duve首次提出细胞自噬的生物学概念:细胞在缺乏营养和能量供应时，部分细胞质与细胞器被包裹进一种特异性的双层膜或者多层膜结构的自噬体(autophagosome)中，形成的自噬体再与
3、溶酶体(Lysosome)融合形成自噬溶酶体(autolysosome)，胞质和细胞器成分在这里被降解为核苷酸、氨基酸、游离脂肪酸等小分子物质，这些小分子物质可以被重新利用合成大分子或者合成ATP。,Autophagy,autophagy is a process by which cells undergo partial autodigestion that prolongs survival for a short time under starvation conditions.It provides nutrients that are necessary to maintain c
4、ell viability.autophagy is also involved in the killing of bacteria that are ingested by cells.细胞生存的一种机制,在很多生理过程如清除损伤、衰老细胞器以及冗余蛋白上发挥着重要作用,Autophagy,细胞正常生理活动中，自噬维持在一个非常低的水平保持细胞稳态细胞处于饥饿和营养因子缺乏环境、进行结构调整、降解胞内代谢产物及损伤细胞器时，细胞内的自噬水平迅速上调,Autophagy is activated by,Changing of environmental conditions:starvati
5、on conditions associated with deficiency of nutrients such as amino acids;hypoxic conditions;high temperaturesCellular remolding:during development and differentiation（诱导因素：营养和能量缺乏、氧化应激、感染、蛋白质大量聚集）,Autophagy,通过自噬,细胞可以在饥饿条件下存活数天甚至数周过度激活的自噬引起细胞发生程序性死亡型程序性死亡（凋亡型程序性死亡）Determination of lifespanPreventing
6、 certain types of disease:contribute to some pathologies近年来由于酵母自噬突变株的产生，使自噬分子基础的研究有很大的进展,Autophagy,细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程，是真核细胞特有的生命现象细胞内物质的两种降解途径：蛋白酶体系统：降解胞内的短寿命蛋白自噬作用：长寿命蛋白和一些细胞器的降解利用,the proteasome breaks down ubiquitinated proteins,but it may not recognize misfolded proteins and protein aggr
7、egates,细胞自噬过程,自噬体膜：来源：粗面内质网的非核糖体区域高尔基体一种新合成的结构被降解物：部分胞浆细胞内需降解的细胞器(线粒体)细胞内需降解的蛋白质,细胞自噬过程,饥饿、氧化应激损伤自噬体膜脱落，形成环状分隔膜，包绕在被降解物周围分隔膜逐渐延伸，将要被降解的胞浆成分完全包绕形成自噬体（autophagosome）自噬体通过细胞骨架微管系统运输至溶酶体，与之融合形成自噬溶酶体(autolysosome),并降解其内成分，自噬体膜脱落再循环利用,自噬的分类,微自噬:包绕底物的是自身发生内陷的溶酶体膜巨自噬:即通常所指的自噬,胞质被来源于内质网的非核糖体区域、高尔基体等脱落的双层膜所包绕
8、CMA:胞浆内蛋白结合到分子伴侣后转运到溶酶体腔中,被溶酶体酶消化,自噬的功能,对外源性刺激(包括营养缺乏、细胞密度负荷、低氧、氧化应激、感染等)的适应性反应：降解产物氨基酸、核苷酸、游离脂肪酸等可供物质能量循环细胞保持稳定状态的管家机制：调控长寿命蛋白、过氧化物体、线粒体和内质网的更新参与一定的组织特异性融合 一种防御机制:清除胞质内受损的细胞器、代谢产物,进行亚细胞水平上的重构,保护受损的细胞；作为一种细胞死亡程序诱导细胞主动性死亡,自噬的生理学意义,自噬在生理过程的作用：参与发育和分化过程中机体的重新构建(remomding)营养缺乏时产生氨基酸清除不需要的、损伤的细胞器与分子,细胞自噬
9、的分子机制,参与自噬体形成的两个泛素样蛋白系统：分别由Atg3、Atg5、Atg7、Atg10、Atg12和LC3参与组成Atg12 首先由E1 酶 Atg7 活化，之后转运至 E2 酶 Atg10，最后与Atg5 结合,形成自噬体前体(autophagosomal precursor)；LC3-也被 Atg7 活化，转运至第二种 E2 酶 Atg3，并被修饰成膜结合形式 LC3-。LC3-定位于前自噬体和自噬体自噬体的标志分子（LC3 是酵母细胞自噬相关基因 Atg8 的类似物）,细胞自噬的分子机制,型磷脂酰肌醇三磷酸激酶（ClassPI3K）PI3 kinase type III,whic
10、h includes Atg6 in its complex,promotes the nucleation of autophagic vesicles.,自噬的生理和病理意义,广泛存在于正常的生理过程中：如清除细胞废物、结构重建、生长分化等细胞对不良环境的一种防御机制：如对抗营养缺乏、电离辐射参与多种疾病的病理过程：无论是自噬过度还是自噬不足都可能导致疾病发生,Physiological Functions of Autophagy,Autophagy Defends against Metabolic StressAutophagy Works as a Cellular Houseke
11、eperAutophagy May Be a Guardian of the GenomeAutophagy in Life and Death Decisions of the Cell,1.Autophagy Defends against Metabolic Stress,Autophagy is activated as an adaptive catabolic process in response to different forms of metabolic stress:nutrient deprivationgrowth factor depletionhypoxia,2.
12、Autophagy Works as a Cellular Housekeeper,Housekeeping functions performed by autophagy includes:the elimination of defective proteins and organelles the prevention of abnormal protein aggregate accumulation the removal of intracellular pathogensCritical for autophagy-mediated protection against agi
13、ng,cancer,neurodegenerative diseases,and infection,3.Autophagy May Be a Guardian of the Genome,Autophagy-defective cells:genomic instability.Related to:failure to control the damage of checkpoint or repair proteins,deregulated turnover of centrosomes,insuficient energy for proper DNA replication and
14、 repairexcessive generation of reactive oxygen species due to ineficient removal of damaged mitochondriaThe precise mechanisms are unclear,4.Autophagy in Life and Death Decisions of the Cell,Autophagy can independently inluence life and death decisions of the cell(by being cytoprotective or selfdest
15、ructive),it is also intricately linked to apoptotic death pathwaysFactors that may control the cellular“decision”between the autophagy and apoptosis include:potentially variable thresholds for each processmolecular links that coordinately regulate apoptosis and autophagymutual inhibition or activati
16、on of each pathway by the other,Autophagy in Disease,Autophagy and Neurodegenerative DiseasesAutophagy and Liver DiseaseAutophagy and Muscle DiseaseAutophagy and Cardiac DiseaseAutophagy and CancerAutophagy and AgingAutophagy in Infection,Immunity,and Inlammatory Diseases,1.Autophagy and Neurodegene
17、rative Diseases,Autophagy functions as a quality-control system that targets oligomeric(低聚物,低聚体)proteinsSubstrates need to be unfolded to pass through the narrow pore of the proteasomal barrel,oligomeric and aggregated proteins are poor substrates for proteasomal degradation and better targets for a
18、utophagic degradationAutophagy activation reduces the formation of protein aggregates and the neurotoxicity of aggregate-prone proteins,2.Autophagy and Liver Disease,Protein quality-control function may be important in the pathogenesis of the most common genetic cause of human liver diseaseA broader
19、 question of biomedical relevance is whether the protein quality-control function of autophagy plays a more general role in protecting the liver against alcohol and other hepatotoxic agents,3.Autophagy and Muscle Disease,Pathogenesis of myodegenerative diseases involve:the failure of autophagosomes
20、to fuse with lysosomesthe aggregation of misfolded proteins that exceed the autophagic clearance capacity of the myocyte,4.Autophagy and Cardiac Disease,Autophagy may constitute an important physiological or pathophysiological response to cardiac stresses ischemia or pressure overloadcoronary artery
21、 diseasehypertensionaortic valvular diseasecongestive heart failureCardiomyocyte(similar to the neuron)is a postmitotic cell in which basal autophagy may be important in protein and organelle quality control,5.Autophagy and Cancer,Autophagy is a tumor suppressor pathwaystrong correlation between：mol
22、ecules that are involved in autophagy induction and tumor suppression molecules that are involved in autophagy inhibition and oncogenesis,细胞自噬与肿瘤,自噬对于肿瘤细胞存在双向效应 肿瘤发展不同阶段、组织类型、细胞分化状态、周围环境以及特定的基因特征和信号转导途径共同影响着自噬的活性和结果,细胞自噬与肿瘤,Autophagy and AgingAutophagy in Infection,Immunity,and Inflammatory Diseases,存在问题,自噬体膜的来源自噬的调节机制自噬与程序性死亡的关系等,Autophagy and apoptosis,
