动物模型
动物模型的概念
动物模型的概念动物模型是指利用动物作为研究对象，以模拟人类疾病或生理过程的实验方法。
在医学、生物学和药物研发等领域，动物模型被广泛应用于疾病机制研究、药物筛选和治疗效果评估等方面。
通过对动物模型的研究，科学家们可以更深入地了解疾病的发生机制，寻找新的治疗方法，并评估治疗效果。
动物模型的应用起源于古代。
早在公元前400年，亚里士多德就开始使用动物进行实验研究。
而现代动物模型的建立则主要始于20世纪。
在之后的几十年里，科学家们不断开发和完善各种动物模型，以满足不同领域的研究需求。
常见的动物模型包括小鼠、大鼠、猪、狗、猴等。
选择哪种动物模型取决于研究目的和所研究的疾病或生理过程的特点。
例如，小鼠是最常见的动物模型之一，其具有生育力强、寿命短、易于育种等优点，非常适用于基因功能研究和药物筛选。
而猪则因其解剖结构和生理功能与人类较为相似，成为心血管疾病、消化系统疾病等研究的理想模型。
动物模型的建立需要经过严格的实验设计和伦理审查。
在进行动物实验之前，科学家们必须制定详细的实验方案，确保实验目的明确、实验过程严谨，并保证动物的福利不受伤害。
伦理审查委员会会对实验方案进行评审，并根据动物福利法规对实验进行监督。
动物模型的优缺点需要充分考虑。
虽然动物模型在科学研究中具有重要的地位，但也存在一些限制。
首先，动物模型与人类生物学和疾病机制存在差异，因此研究结果可能无法完全适用于人类。
其次，动物模型的建立和维护需要大量的时间、金钱和资源。
此外，动物实验也涉及伦理和道德问题，需要权衡动物利益与科学研究的价值。
近年来，随着生物技术的进步，越来越多的替代方法被用于替代或减少动物实验。
例如，体外细胞实验、计算机模拟和人体器官芯片等技术的发展，为人类疾病研究提供了新的途径。
然而，目前这些替代方法仍然无法完全替代动物模型，仍需依赖动物模型进行深入研究。
总的来说，动物模型作为一种重要的研究工具，对于疾病机制研究、药物研发和治疗效果评估都具有重要意义。
动物模型
四、严重联合免疫缺陷小鼠 （Sever Combined Immunodeficient Mice, SCID mice） ）
江苏大学
1983年 Bosma首次报告 来源于 年 首次报告,来源于 小鼠。 首次报告 来源于C.B-17小鼠 。 小鼠 由于第16对染色体隐性基因突变， 由于第 对染色体隐性基因突变，纯合突变导致 对染色体隐性基因突变 淋巴细胞抗原受体基因VDJ区域重排的重组酶活 淋巴细胞抗原受体基因 区域重排的重组酶活 性异常，基因重排时断裂无法正常连接， 性异常，基因重排时断裂无法正常连接，从而影 细胞的正常功能分化。 响B、T细胞的正常功能分化。 、 细胞的正常功能分化 1988年我国医科院动物所从美国 年我国医科院动物所从美国Jackson实验 年我国医科院动物所从美国 实验 室引进； 室引进；
肿瘤移植瘤模型在临床肿瘤学中的意义 肿瘤移植瘤模型在临床肿瘤学中的意义 临床肿瘤学
建立平行模型，明确诊断和跟踪预后。 诊断和预后 ：建立平行模型，明确诊断和跟踪预后。 个体化疗有效试验：对于晚期和复发肿瘤有重要意义。 个体化疗有效试验：对于晚期和复发肿瘤有重要意义。 药物有效的标准： 肿瘤不生长 肿瘤不生长； 肿瘤生长缓慢 肿瘤生长缓慢； 肿瘤长出 药物有效的标准：1.肿瘤不生长；2.肿瘤生长缓慢；3.肿瘤长出 后又消失； 肿瘤无转移 肿瘤无转移； 动物寿命延长 动物寿命延长。 后又消失；4.肿瘤无转移；5.动物寿命延长。
动物模型
动物模型的分类
1.自发性动物模型 2.诱发性性动物模型 3.抗疾病型模型 4.生物医学动物模型
是指研究者通过使用物理的、 是指实验动物未经任何有意识 化学的、生物的和复合的致病 的人工处置，在自然情况下所 因素作用于动物，造成动物组 发生的疾病。或由于给予突变 织、器官或全身一定的损害， 的异常表现通过遗传育种手段 是指特定的疾病不会在 出现某些类似人类疾病时的功 保留下来的动物模型 某种动物身上发生。 能、代谢或毒使动物患相应的 传染病。 是指利用健康动物的生物血 特征来提供与人类疾病相似 的表现的疾病模型。
实验动物模型设计原则
实验动物模型设计原则全文共四篇示例，供读者参考第一篇示例：实验动物模型设计原则是指在科学研究中利用动物进行实验时，设计合理的动物模型以保证实验结果的准确性和可靠性的原则。
在设计动物模型时，需要考虑到动物的种类、数量、性别、年龄、体重等因素，以及实验目的、方法和流程等因素。
下面将详细介绍实验动物模型设计的原则。
一、选择合适的动物种类在设计动物模型时，首先需要选择符合实验要求的动物种类。
不同的实验需要不同的动物种类，如小鼠、大鼠、猪、猫、狗等。
选择动物种类时需要考虑到动物的生理特征、行为特征、易于处理的程度、成本等因素，以保证实验的准确性和可靠性。
二、确定合适的动物数量在设计动物模型时，需要确定合适的动物数量。
动物数量的确定需要考虑到实验的目的、实验的统计学要求、实验的时间和成本等因素。
通常情况下，实验动物的数量应该足够大以确保实验结果的可靠性和统计学意义。
四、注意动物的生活质量和福利在设计动物模型时，需要注意动物的生活质量和福利。
实验动物应该得到良好的饲养环境和适当的饲料，以确保它们的健康和舒适。
应该减少对实验动物的痛苦和苦难，确保动物的福利。
五、避免不必要的动物实验在设计动物模型时，需要避免不必要的动物实验。
不应该进行无关紧要或冗余的动物实验，以免浪费动物资源和造成不必要的伤害。
应该充分考虑实验设计和实验方法，以减少对动物的实验数量和强度。
六、确保实验的可重复性和可比性在设计动物模型时，需要确保实验的可重复性和可比性。
实验应该具有较高的稳定性和可再现性，以便其他研究者能够复制实验结果。
应该充分考虑实验的控制变量和实验的质量控制，以确保实验结果的可信度。
七、密切关注实验动物的行为和生理指标在设计动物模型时，需要密切关注实验动物的行为和生理指标。
应该充分了解动物的行为特征和生理状态，以确保实验结果的准确性和可靠性。
应该选择合适的实验方法和技术手段，以评估动物的行为和生理指标。
实验动物模型设计是科学研究的重要环节之一，对实验结果的准确性和可靠性起着至关重要的作用。
实验动物学——第七章动物模型
4．生物医学动物模型（Biomedical Animal Model） 生物医学动物模型是指利 用健康动物生物学特征来提供人类疾病相似表现的疾病模型。兔甲状旁腺分布比 较分散，位置不固定，有的附着在主动脉弓附近，摘除甲状腺不影响甲状旁腺功 能，是摘除甲状腺实验较理想的动物模型；如沙鼠缺乏完整的基底动脉环，左右 大脑供血相对独立，是研究中风的理想动物模型；鹿的正常红细胞是镰刀形的， 多年来被供作镰刀形红细胞贫血研究；兔胸腔的特殊结构用于胸外手术研究比较 方便。但这类动物模型与人类疾病存在着一定的差异，研究人员应加以分析比较。
诱发性动物模型的特点在于制作方法简便，实验条件容易控制，复制的模型 符合研究目的，短时间内可以复制大量的动物模型，特别适用于药物筛选。但其 不足之处是诱发性动物模型与自然疾病存在着某些不同，例如诱发性肿瘤与自发 性肿瘤对抗癌药物的敏感性不同。而且有些人类疾病不能用人工方法诱发成功。
2．自发性动物模型（Spontaneous Animal Model） 自发性动物模型是指实验 动物未经任何人工处置，动物自然发生的疾病，或由于基因突变，通过遗传育种 保留下来的动物模型。主要包括突变系的遗传疾病模型和近交系的肿瘤疾病模 型。
（1）遗传疾病动物模型。 突变系的遗传疾病很多，可分为代谢性疾病、分子 性疾病、特种蛋白合成异常性疾病等，如裸鼠、肥胖小鼠、高血压小鼠等。
（2）肿瘤疾病动物模型。 近交系肿瘤动物模型随实验动物种属、品种不同， 肿瘤的发生类型和发病率有很大差异。
动物模型
REVIEWContribution of the inflammasomes to autoinflammatory diseases and recent mouse models as research tools ☆Michael C.Heymann ⁎,Angela Rösen-Wolff ⁎Department of Pediatrics,University Hospital Carl Gustav Carus,Fetscherstrasse 74,01307Dresden,GermanyReceived 22August 2012;accepted with revision 15January 2013Available online 4February 2013KEYWORDSInnate immune system;Danger signal;Recurrent feverAbstract Inflammasomes are multiprotein complexes that serve as activating platforms for the enzyme caspase-1in response to various danger signals.Active caspase-1can cleave the precursors of the pro-inflammatory cytokines IL-1βand IL-18and thereby activate them.Deregulation of this cascade caused by mutations in genes coding for inflammasomal components and their interaction partners can lead to severe disease.This review summarizes the contribution of deregulated inflammasomes to the field of autoinflammatory syndromes.In addition,it gives insight into currently available mouse models that are used to study and characterize the role of the inflammasome components in the pathophysiology of these diseases.©2013Elsevier Inc.All rights reserved.Contents 1.Introduction .........................................................1762.The concept of “autoinflammation ”............................................1762.1.The cryopyrin associated periodic syndromes (CAPS)...............................1772.2.Other inflammasome components..........................................1782.3.Familial Mediterranean Fever (FMF)........................................1782.4.Pyogenic arthritis,pyoderma gangrenosum,and acne syndrome (PAPA)....................1782.5.Metabolic diseases associated with inflammasomes ................................1793.Animal models ........................................................1793.1.NLRP3..................................... (180)☆The authors are employees of the University Hospital Carl Gustav Carus in Dresden,Germany.Their work is supported by the German Research Foundation (Klinische Forschergruppe KFO 249,project TP1,RO/471-11and TP2,HO 4510/1-1),and the PID-NET project of the Federal Ministry of Education and Research (project A4),and they report no financial conflict of interest.⁎Corresponding authors.Fax:+493514586333.E-mail addresses:michael.heymann@uniklinikum-dresden.de (M.C.Heymann),angela.roesen-wolff@uniklinikum-dresden.de (A.Rösen-Wolff).1521-6616/$-see front matter ©2013Elsevier Inc.All rights reserved./10.1016/j.clim.2013.01.006a v a i l ab l e a t w w w.sc i e n c ed i re c t.c o mC l i n i c a l I m m u n o l o g yw w w.e l s e v i e r.c o m /l o c a t e /y c l i mClinical Immunology (2013)147,175–1843.2.Pyrin..........................................................3.3.(Pro)caspase-1....................................................4.Conclusions......................................................... Conflict of interest statement.................................................. References..............................................................1.IntroductionTen years after their discovery[1],inflammasomes are more than ever believed to play a central role in the recognition of exogenous and endogenous danger signals.In addition to other intracellular pattern-recognition receptors(PRRs),including Nod-like receptors(NLRs)[2],C-type lectin receptors(CLRs) [3,4],and the RIG-like receptors(RLRs),which are capable of sensing RNA[5],these multiprotein complexes contribute to intracellular identification of potentially harmful substances, bacteria,or viruses.Inflammasome activation initiates effec-tive defense mechanisms against potential threads.Inflammasomes typically consist of i)a characteristic scaf-folding protein,ii)the small adapter molecule ASC(apoptosis-associated speck-like protein containing a CARD domain) [6],and iii)the progenitor form of the enzyme caspase-1 (procaspase-1)which is responsible for the activation of pro-inflammatory cytokines such as interleukin-1β(IL-1β)or IL-18[1,7–10].Caspase-1is activated through autoprocessing in response to inflammasome assembly[10].Subsequent secretion of IL-1βand IL-18results in stimulation,proliferation and differentiation of T and B cells which participate in the immunological response to challenging threads[11].To date,four scaffolding proteins that contribute to inflammasome assembly have been described.Thus,four different inflammasomes are capable of sensing a wide range of danger signals.1)The NLRP1(NOD-like receptor family, pyrin domain containing1)inflammasome is activated by muramyl dipeptide(MDP)and lethal toxin from Bacillus anthracis[12,13].2)The AIM2(Absent in melanoma2) inflammasome can sense cytoplasmic dsDNA(double stranded deoxyribonucleic acid)[14],and3)the NLRC4(NLR family CARD[Caspase activation and recruitment domain]domain containing protein4)inflammasome recognizes flagellin [15,16],another bacterial protein.The fourth inflammasome is the NLRP3(NOD-like receptor family,pyrin domain containing3)inflammasome,which is responsible for IL-1βactivation following various stimuli.Inflammasome assembly in general is realized by the binding of ASC to the scaffolding proteins via interaction of the pyrin domain(PYD)of ASC and the PYD of the respective scaffolding protein.Due to the fact that ASC also harbors a caspase-1recruitment domain(CARD)domain,it can bind procasapase-1simultaneously,leading to the assembly of the multiprotein complex.Notably,NLRC4can bind procaspase-1 directly through the interaction of its CARD domain with the CARD domain of procaspase-1[17].In this case,the partici-pation of ASC does not seem to be necessary but may stabilize the inflammasome complex[7].Due to the intriguingly large number of stimuli that can activate the NLRP3inflammasome,it has an exceptional position among the inflammasomes.NLRP3activating stimuli include bacterial proteins,such as MDP[18],pore forming substances including nigericin[19],toxins such as alpha-toxin of Staphylococcus aureus[20],bacterial RNA[21], viruses[22],or fungi[23–25].Also other danger associated molecular patterns(DAMPs)including asbestos[26],alum [27],urate crystals[28],extracellular adenosintriphosphate (ATP)[19],UV-radiation[29],or potassium(K+)-efflux[30] result in NLRP3activation and subsequent IL-1βand IL-18 release.Since the variety of stimuli activating the NLRP3 inflammasome appears to be rather large for one receptor protein,the search for the“real”activator or further molecules that might become activated upstream of NLRP3is an ongoing challenge.Reactive oxygen species(ROS)generated in response to cell stress have been postulated to be activating stimuli for the NLRP3inflammasome[31].However,ROS may also play a role in boosting the expression of several genes,including the genes encoding NLRP3,pro-IL-1βand procaspase-1. Thus,ROS inhibition hypothetically impairs the production of inflammasomal proteins[32].Lysosomal rupture together with cathepsin release into the cytoplasm could also be an alternative upstream event prior to NLRP3activation[27,33].Notably,a constantly growing number of proteins that may be part of inflammasomes have been discovered.Recently, the RIG-I(Retinoic acid-inducible gene-I)inflammasome as an RNA sensor and IFI16(Interferon gamma-inducible protein 16),recognizing nuclear viral DNA,were postulated as new members of the inflammasome family[34–37].2.The concept of“autoinflammation”The concept of“autoinflammation”was first proposed by McDermott and Kastner in1999[38]in a publication elucidating mutations in TNFRSF1A to be responsible for the hereditary inflammatory disease tumor necrosis factor (TNF)-receptor associated periodic syndrome(TRAPS;OMIM #142680)[38].In1997mutations in the MEFV gene had already been identified in patients suffering from Familial Mediterra-nean Fever(FMF;OMIM#249100)[39].In contrast to auto-immune reactions,the inflammatory episodes of these diseases seem to be unprovoked,high-titer autoantibodies are absent and neutrophils and macrophages rather than T or B lymphocytes constitute the involved cell types[38,40,41].A refined definition of autoinflammatory diseases as disorders with“abnormally increased inflammation,mediated predom-inantly by the cells and molecules of the innate immune system,with significant host predisposition”[40]emphasizes the role of the innate immune system in autoinflammation distinguishing it from autoimmunity.In this context,McGonagle and McDermott categorized a continuum of inflammatory diseases with autoinflammatory disorders on the one end and autoimmune disorders on the other end of the spectrum[42]. Monogenic autoinflammatory disorders such as TRAPS or FMF180180180180181176M.C.Heymann,A.Rösen-Wolffare described as “maybe exclusively determined by local tissue-specific factors ”[42]whereas the adaptive immune system mainly seems to determine rare monogenic autoim-mune diseases,such as ALPS (autoimmune lymphoproliferative syndrome),IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome)or APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy)[42].Disorders classified in the central range of the continuum are characterized by the influence of both the innate and the adaptive immune system [42].Polygenic autoinflammatory diseases such as Crohn disease or gout,mixed pattern diseases such as psoriasis or Behcet disease and classic polygenic autoimmune diseases such as rheumatoid arthritis or Sjögren syndrome are covered by this continuum [42].In addition to FMF and TRAPS,other autoinflammatory hereditary monogenic diseases have been explored.Due to the fact that activation of inflammasomes is the initial step in the maturation of biologically active forms of the pro-inflammatory cytokines IL-1βand IL-18,it appears obvious that a deregulation of this cascade can cause immune-deregulation and severe autoinflammatory diseases.Accordingly,mutations in several components of inflamma-somes or in inflammasome associated molecules can cause autoinflammatory diseases.Fig.1summarizes the autoin-flammatory syndromes that are associated with inflammasomal components.2.1.The cryopyrin associated periodic syndromes (CAPS)The autoinflammatory diseases caused by mutations in NLRP3,the gene which encodes cryopyrin (=NLRP3),are defined asCAPS [43].Deregulated activation of NLRP3inflammasomes causes secretion of highly enhanced levels of bioactive IL-1β[44,45].This increased production of mature IL-1βis possibly induced by a spontaneous or constitutive assembly of NLRP3molecules which leads to inflammasome activa-tion [46,47].However,the particular signals triggering disease in CAPS patients have not been completely eluci-dated [41].To date,three CAPS subtypes are distinguished.They differ in severity although similar symptoms such as fever,urticarial skin rash or elevated acute-phase response [48]point to the continuum of the clinical characteristics of CAPS [48,49].The less severe manifestation of CAPS is familial cold autoinflammatory syndrome (FCAS;OMIM #120100)[50].The symptoms are triggered by cold and do not only include recurrent febrile episodes but also urticarial rash,arthral-gia,conjunctivitis,and headache.Severe long term damage induced by amyloidosis is very rare [43].Patients with Muckle –Wells syndrome (MWS;OMIM #191900)[50,51]additionally suffer from inflammation of the inner ear which can lead to complete hearing loss.The disease is not mainly triggered by cold.Amyloidosis is more frequent than in FCAS patients and the most fatal and dangerous complication of the disease [43,52].Neonatal-onset multisystem inflammatory disease (NOMID;also CINCA;OMIM #607115)[53]has the most severe impact on the affected individual.Serious inflammation of the central nervous system leads to various impairments including hearing loss and loss of vision both due to progressive damages of the respective nerves.In addition,NOMID is also accompanied by meningitis,bony epiphysial hyperplasia [54],and mental retardation [43,55,56].Figure 1How deregulated inflammasomes lead to enhanced pro-inflammatory signals.After activation,NLRP3interacts with ASC which can subsequently interact with procaspase-1.Pyrin and PSTPIP1do also play a role in inflammasome control.Their contribution is not completely understood yet.After inflammasome assembly,activated caspase-1can cleave pro-IL-1βand pro-IL-18into their active mature variants.Mutated versions of certain proteins lead to different autoinflammatory diseases:NLRP3alterations cause CAPS,PSTPIP1mutations cause PAPA and pyrin alterations lead to FMF.Genetic variants of caspase-1have also been associated with autoinflammatory phenotypes.However,this link needs further studies.ASC:Apoptosis-associated speck-like protein containing a CARD domain;CAPS:Cryopyrin associated periodic syndromes;FMF:Familial Mediterranean Fever;IL-1β:Interleukin-1β;IL-18:Interleukin-18;NLRP3:NOD-like receptor family,pyrin domain containing 3;PAPA:Pyogenic arthritis,pyoderma gangrenosum,and acne syndrome;PSTPIP1:Proline –serine –threonine phosphatase-interacting protein 1.177Contribution of the inflammasomes to autoinflammatory diseases and recent mouse models2.2.Other inflammasome componentsBesides NLRP3,other inflammasome components have been associated with different diseases.One interesting connection between an inflammasome component and autoinflammatory symptoms was recently elucidated by Luksch and colleagues[57].They found several genetic variants of CASP1,the gene encoding procaspase-1,in patients suffering from symptoms similar to autoinflammatory disorders but who did not have any mutation in the respective genes.These genetic alterations of CASP1lead to altered protein structure,expression levels and/or decreased enzy-matic activity resulting in less or abolished IL-1βmaturation. Nevertheless,these reduced levels of IL-1βdid not prevent hyperinflammation[57].It is still open if these CASP1variants cause autoinflammatory conditions.Remarkably,Lamkanfi and colleagues showed a contribution of enzymatically inactive procaspase-1to NF-κB(nuclear factor kappa-light-chain-enhancer of activated B-cells)activation via the RIP2 (receptor interacting protein kinase2)pathway[58,59].This could possibly be a mechanism of how genetic variants of the CASP1gene may contribute to autoinflammatory phenotypes.Genetic variants of AIM2and NLRP1have been linked to diseases,which are not classically proposed as autoinflam-matory.Nonetheless,these associations show the importance of a proper regulation of inflammasomal activity.Inactivation of AIM2,has been linked to colorectal cancer [60]suggesting a tumor suppressor function of the protein. However,a recent publication described AIM2overexpression as putative promoting factor for the development of oral squamous cell carcinoma(OSCC)[61].A relation between mutations in AIM2or altered expression in autoinflammatory diseases is yet uncharacterized.For NLRP1,associations have been made between certain single nucleotide polymorphisms (SNPs)in the NLRP1gene and generalized vitiligo[62,63]and celiac disease[64],both polygenic disorders with yet poorly understood pathophysiology.2.3.Familial Mediterranean Fever(FMF)Mutations in the gene MEFV,which encodes pyrin(also known as marenostrin),are responsible for the most common hereditary autoinflammatory disease FMF[39].Patients suffer from unprovoked febrile episodes and also inflammation of the skin,notably peritonitis,arthritis,synovitis,and serositis [56,65].In most patient families the disease exhibits a recessive trait which means that both alleles of the gene have to be mutated for the clinical manifestation of the syndrome [66].However,about20%of the FMF patients do not have remarkable mutations in the respective gene.This indicates existing mutations which are either more difficult to detect or are present in other genes leading to clinical FMF[65–67].Based on the fact that FMF is described as an autosomal recessive disease[65],it had been assumed that the pyrin protein may serve as a negative regulator of inflammasome activity.Pyrin comprises five domains[68],including a PYD and the B30.2domain,both involved in the putative negative regulatory effect.First,it has been shown that pyrin interacts with the adaptor protein ASC via their PYD domains[69–72].ASC is necessary for activation of at least the AIM2and the NLRP3 inflammasomes and maybe also for activation of the NLRP1 inflammasome in some cases[7].Capturing of ASC by pyrin could be a mechanism how inflammasome activity is con-trolled.This mechanism may be impaired in patients with mutated pyrin protein[73].Second,it has been shown that overexpressed B30.2 domain can interact with caspase-1and inhibit its enzymatic activity[71].Interestingly,most mutations in FMF patients cluster in the B30.2coding region[66].Accordingly,mutated B30.2has reduced binding capacities to caspase-1[71,74]. This could result in less caspase-1control and thereby in increased caspase-1activity.In contrast to the controlling function of pyrin,Yu and colleagues[75]demonstrated an enhanced inflammasome activation by overexpressing the B30.2domain[75].Accord-ingly,a knock-down of pyrin by siRNA resulted in less caspase-1activity[76].Binding ASC or NLRP3via PYD–PYD interaction could point to a supporting role of pyrin in inflammasome activation[77].However,Chae and colleagues created a mouse model in which gain-of-function mutations in pyrin caused severe inflammation depending on ASC but independent of NLRP3[78].This could serve as a hint for an inflammasome-like complex containing pyrin as a backbone but lacking NLRP3[78].Pyrin may promote IL-1βmaturation as a part of a so called pyroptosome,together with caspase-1 and ASC[75].These two opposite functions of pyrin illustrate the still incompletely understood pathogenesis of FMF.However,more studies will be necessary to finally reveal the functions and respective pathways of pyrin.2.4.Pyogenic arthritis,pyoderma gangrenosum, and acne syndrome(PAPA)PAPA(OMIM604416)[79]is another autoinflammatory disease which is indirectly associated with pyrin.Patients suffer from severe inflammation of the skin including pyoderma gangrenosum,skin ulcerations or cystic acne[80].Inflamma-tion of the joints and recurrent febrile episodes,which can occur about1–3days every month,are further characteristics of the syndrome[56].In the case of PAPA,the respective mutations are not located in the pyrin encoding gene MEFV but in the PSTPIP1 gene,which encodes a cytoskeleton organizing protein with the same name,PSTPIP1[81,82].These altered protein molecules exhibit an increased ability to interact with pyrin.A putative contribution of pyrin to inflammation via inflammasome or pyroptosome activation and elevated IL-1βmaturation has been published[75].PSTPIP1could serve as a regulator of pyrin activity.A first possible mechanism to explain hyperinflammation in PAPA patients is enhanced recruitment of pyrin to ASC mediated by PSTPIP1[80,83]. Longer and increased association between mutated PSTPIP1 and pyrin could lead to enhanced secretion of IL-1βand thus to increased inflammation[56,80].Second,PSTPIP1itself could be a regulator of inflammasome or pyroptosome activity.Prolonged interaction with pyrin could cause altered intracellular distribution of PSTPIP1.This would in return lead to deregulated pyroptosome or inflammasome activity[80,83,84].178M.C.Heymann,A.Rösen-WolffThird,concerning a putative role of pyrin as a negative regulator of inflammasome activity,increased binding of pyrin to PSTPIP1may impair the regulatory effect of pyrin on inflammasomes[85].All these possibilities show the necessity of further studies concerning pyrin,PSTPIP1and their contribution to FMF and PAPA pathophysiology.2.5.Metabolic diseases associated with inflammasomesIn the past years,more and more diseases which are not typically considered autoinflammatory syndromes have been associated with a deregulation of inflammasome activity and IL-1βmaturation.Gout is the first example(OMIM#300323).Patients suffer from sudden inflammation of the joints[77].Deposition of monosodium urate(MSU)crystals leads to inflammation of joints and periarticular tissue[28].Jürg Tschopp's group in Lausanne explored the NLRP3inflammasome as key player in the pro-inflammatory signaling that follows the recognition of MSU crystals.Peritoneal macrophages of mice lacking the proteins ASC,procaspase-1or NLRP3,which represent components that are necessary for the formation of the NLRP3-inflammasome,did not secrete mature IL-1βafter incubation with MSU,in contrast to peritoneal macrophages of wild-type mice.Additionally,none of the toll-like receptors (TLRs),which are usually responsible for sensing danger signals at the cell surface,showed significant influence on MSU sensing.Challenging single or TLR2/4double knock-out (KO)mice with MSU did not inhibit inflammation[86].Instead, phagocytosis of the crystals seems to be an important incident for IL-1βactivation after MSU exposure,including the participation of cathepsin B,ROS and the efflux of potassium ions[27,77].Finally,the successful treatment of patients suffering from gout with recombinant IL-1receptor antagonist once more underlined the association of gouty attacks with the inflammasomes[87,88].In addition,type II diabetes(OMIM#125853)has already been linked to IL-1βsince the1980s[89]and recent studies reinforced this link[90,91].Development of type II diabetes is one of the major risks of obesity and exposure to certain molecules which are present at elevated levels in obese patients stimulates inflammasome activation and leads to IL-1βand IL-18mediated inflammation.Those factors include cholesterol crystals[92],free fatty acids[93]and ceramides [94].Patients of type II diabetes show a characteristic insulin resistance and a lack in insulin secretion caused by dysfunc-tional islet beta cells in the pancreas.This in turn leads to increased levels of glucose in the circulating blood[95].Pancreatic cells from type II diabetes patients exhibit amyloid deposits[96].Especially islet amyloid peptide(IAAP) was shown to activate NLRP3and caspase-1.It further co-localized with ASC after inflammasome activation[95]. The subsequently secreted IL-1βled to impaired functionality and viability of beta cells[95].Finally,blockade of IL-1receptor in a clinical study led to a decrease of inflammatory markers in type II diabetes patients and improved the secretory potential of the beta cells[91].Notably,clinical trials of IL-1βblockade in patients with type I diabetes revealed a slowdown in the course of the disease and prevention of an additional decline of beta cell functionality[97,98].In conclusion,the contribution of the inflammasomes to other inflammatory and autoimmune diseases has become obvious.Further research is required to uncover the complex details in signal transduction leading to uncontrolled inflam-mation.Maybe future studies will reveal further diseases in which IL-1βand IL-18play an important pathophysiological role.3.Animal modelsTo further characterize the role of certain proteins in inflam-mation,mouse models appear to be valuable tools.Several manipulations of the murine genome can be performed in order to resemble human disease.1)Disruption of single genes in so-called“knock-out”(KO)mice can be used to imitate nonsense mutations with a loss of protein.2)Knock-in (KI)models harbor artificially introduced genes with or without mutations.Additionally,conditional KO or KI models can provide valuable information about the effect of the respective gene in certain tissues or cell types by using the cre/loxP-system under tissue or cell type specific promoters.In order to introduce a gene,transgenic models or gene-target models could be used.Applying the transgenic technology,the gene may insert at any locus of the genome, whereas the gene-target method ensures the insertion at a specific locus.Introduced gene mutations can result in1)reduced tran-scription of the gene,2)the truncation of protein products and/or3)amino acid exchanges that may affect protein structure or protein function.In order to study the contribution of target genes to the pathophysiology of autoinflammatory disorders,mouse models of different inflammasome components and proteins associat-ed with inflammasome activation have been created(Table1). Table1Contribution of the inflammasomes to autoinflammatory syndromes and selected mouse models. MutatedgeneAffectedproteinAssociatedsyndromeMouse modelsNlrp3NLRP3/cryopyrinFCAS[50]MWS[50,51]NOMID[53]Nlrp3−/−[28]Nlrp3A350V neoR/+[99]Nlrp3L351P neoR/+[99]Nlrp3R258W[100]Nlrp3D301N[101]Casp1(Pro)caspase-1?[57]Casp1−/−Casp11−/−[102]Casp1−/−Casp11tg[103] Mefv Pyrin FMF[39]truncated pyrin[70]KI with mutated humanB30.2domain[78] Pstpip1PSTPIP1PAPA[75,79,81,82]-NLRP3,NOD-like receptor family,pyrin domain containing3;FCAS, Familial Cold Autoinflammatory Syndrome;MWS,Muckle–Wells Syndrome;NOMID,Neonatal-onset multisystem inflammatory disease;FMF,Familial Mediterranean Fever;KI,knock-in;PSTPIP1, Proline–serine–threonine phosphatase-interacting protein1;PAPA, Pyogenic arthritis,pyoderma gangrenosum,and acne syndrome.179Contribution of the inflammasomes to autoinflammatory diseases and recent mouse models3.1.NLRP3NLRP3deficient mice were introduced by Martinon and colleagues in2006[28].The authors documented reduced inflammation in mice deficient of NLRP3when compared to wild-type animals after the administration of MSU crystals.To date,the model has been used in various studies examining whether the inflammation followed by different stimuli was NLRP3dependent[21,22,25,30].Several NLRP3KI models harboring missense mutations are available.The mutations p.A350V[99],p.L351P[99],p.R258W [100],and p.D301N[101]are equivalent to the respective mutations in humans causing CAPS subtypes.Knock-in animals,harboring the mutations p.A350V or p.L351P,develop severe systemic inflammation,causing neonatal or perinatal death[99].The mutation p.A350V led to predominant immigration of neutrophils into different tissues that was accompanied by enhanced levels of various pro-inflammatory cytokines[99].Animals,carrying the mutation p.R258W develop a MWS-like phenotype with skin inflammation,markedly enhanced levels of IL-1β,and a massive systemic expansion of Th17cells[100].Finally,in p.D301N transgenic animals,secretion of IL-1βis massively enhanced,resulting in systemic inflammation. Probably as a result of the inflammation,animals exhibit impaired skeletal growth,which links the mouse model to NOMID[101].3.2.PyrinMost of the mutations in MEFV,the gene that encodes pyrin, are located in the B30.2domain[56,78].In contrast to humans,the murine orthologue lacks this protein domain. Therefore,investigations considering FMF pathogenesis with mouse models turned out to be more complicated.The first animal models analyzed a truncated version of the protein including the complete PYD[70].This protein alteration led to increased caspase-1activation and IL-1βmaturation in homozygous animals.Heterozygous mutations prevented this phenotype and the animals were comparable with wild-type controls[70].Another approach implicated a knock-in strategy of murine pyrin protein fused to a mutated human B30.2 domain as it is present in FMF patients[78].These animals were compared to KO mice deficient in pyrin and several double crossed mice including ASC-KO-and NLRP3-KO-mice. The KI mice harboring the pyrin protein fused to human mutated B30.2variants showed enhanced inflammation and LPS induced IL-1βactivity similar to FMF patients.Moreover, growth retardation,arthritis and dermatitis were also observed in these animals[78].Finally,the inflammatory phenotype was not present in pyrin KO mice and depended on IL-1receptor and ASC expression but not on NLRP3 expression[78].3.3.(Pro)caspase-1The last mouse model that will be discussed in this review deals with the IL-1βconverting enzyme caspase-1.A Casp1KO mouse model has been used in many studies to investigate the role of caspase-1in the immunological response of cells to certain stimuli[102].Unfortunately,the respective Casp1KO mice do not only lack caspaspe-1protein but also caspase-11 [103].Thus,all so far published studies that made use of this mouse model have to be reconsidered carefully.A recent work deals with the contribution of caspase-11 to cell defense against danger signals and pathogens[103]. First,Casp11KO mice were treated with various stimuli to induce an immunological response.Casapase-11was dis-pensable for IL-1βmaturation after stimulation with ATP, flagellin,or dsDNA.In contrast,compared to wild-type animals,Casp11KO mice exhibited a significant reduction in IL-1βsecretion following the exposure to cholera toxinB (CTB),Escherichia coli(E.coli),Citrobacter rodentium,and Vibrio cholerae.Western blot analysis revealed that caspase-1activation failed in Casp11KO mice in response to the latter stimuli[103].For further studies,the scientists introduced the functional Casp11gene isolated from C57BL/6mice into the described caspase-1/caspase-11double KO mice[102,103]to rescue caspase-11expression(=Casp1−/−Casp11tg).In contrast to the double KO mice or Casp11KO mice,the new Casp1−/−Casp11tg animals exhibited enhanced cell death of macrophages and elevated IL-1αsecretion after CTB and E.coli administra-tion.Moreover,the survival of the mice after LPS shock decreased significantly in mice harboring the wild-type transgenic Casp11gene compared to double Casp1−/−Casp11−/−KO mice.In summary,caspase-11seems to play important roles in caspase-1activation and in the response to LPS shock.The protection to LPS induced lethality observed in the classical Casp1/Casp11double KO animals seems to be due to the lack of functional caspase-11and not to the Casp1knock-out,as it had been proposed.The authors postulate a new model, implying caspase-11as an important player in caspase-1 mediated IL-1βand IL-18maturation in response to non-canonical activators.According to these data,the human orthologues caspase-4and caspase-5seem to be more promising targets for medication in sepsis patients than caspase-1[103].4.ConclusionsOver the past decade,the pathophysiology of many recurrent fever syndromes has been linked to increased activity of multiprotein complexes called inflammasomes.However,the molecular mechanisms that result in increased activity of inflammasomes are partially only poorly understood.In addition to spontaneous activation of inflammasomes in autoinflammatory disorders,metabolic diseases can result in inflammasome activation.Thus,further insights into the molecular dynamics of inflammasome activity will lead to a better understanding of multiple diseases,including meta-bolic disorders,and potentially lead to new therapeutics.Undoubtedly,a lot remains to be learned about the complete network of signal cascades ranging from signal recognition to the resulting inflammation.Conflict of interest statementThe authors declare that there are no conflicts of interest.180M.C.Heymann,A.Rösen-Wolff。
构建动物模型的方法
构建动物模型的方法动物模型是生物学、医学以及其他相关领域研究中使用的非常重要的工具。
这些模型能够帮助研究人员更好地分析动物的形态各种复杂的行为特征，并进行实验，以获得新的知识。
构建动物模型的方法有很多，在本文中，我们将介绍一些常见的构建动物模型的方法。
首先，生物学家可以采用“细胞培养”的方法，将多个动物的细胞放入一个培养基中，然后观察不同细胞的发育及其产物的表现。
这种方法通常用于研究各种细胞的发育及其表型，或者用于检测某种物质对细胞发育的影响。
其次，生物学家们也可以采用“模型动物实验”的方法，在实验室中建立各种动物模型，模拟动物的生活。
这种方法的主要目的是为了模拟动物的生活状况，探究动物的各种行为特征，从而为学术研究提供测量和评估数据。
第三，生物学家也可以采用“实时数据采集”的方法来构建动物模型，将相关行为特征的实时数据收集到系统中，以跟踪模型动物的行为和发育特征。
这种方法实时监测模型动物的行为特征，可以获得更多关于动物特征的信息，帮助研究人员更好地了解动物的行为和发育特征。
第四，生物学家也可以采用“实体动物实验”的方法，在实体实验中通过观察模型动物的行为和生理特征，来构建动物模型。
借助实验，研究人员可以更深入地了解动物的行为特征，以及不同环境、温度、营养状况等因素对动物形态和行为特征的影响。
最后，生物学家也可以采用“基因敲除”的方法，分析动物在遗传上的表现型特征，从而构建动物模型。
通过基因敲除，可以发现动物体内特定基因的表达对其行为特征或发育特征的影响。
这种方法对于研究基因调节机制以及基因-行为表型的相互关系很有帮助。
以上就是构建动物模型的几种常见方法。
它们为研究人员提供了有效地检测动物各种行为特征及发育特征的机会，使研究人员可以更深入地了解动物生活状况，从而促进和推进一系列生物学研究。
动物模型
DBA/2
声音
100％发生听源性癫痫
C57
声音
不发生听源性癫痫
年龄和体重的影响： 动物的寿命差异较大，解剖生理特征和反 应随年龄而明显变化，一般幼龄动物比成年动 物敏感，应根据实验要求，选择相应年龄的动 物复制模型（健康动物年龄与体重有相关）。
性别因素的影响： 同种、同品系，不同性别的动物，对某些 反应不一致。 麦角新硷
（2）昼夜不同的影响
实验动物的体温、血糖、基础代谢的、
内分泌等随昼夜的不同呈有节律的变化，
在复制模型时要注意昼夜不同对模型的影
响。
（3）麻醉深度的影响 不同的麻醉药、剂量对动物麻醉效果
有差异，这种差异会影响模型的复制。
（4）手术技巧的影响
手术熟练，将减少对动物的刺激，损伤和出血
能提高模型的成功率。 （5）实验给药的影响 给药途径、剂量和熟练程度不同会对造模产生 影响。
可靠性：复制模型应特异地、可靠地反映该种疾病或 某种机能、代谢、结构变化，同时应具备该种疾病的 主要症状和体征，并经受一系列检测得以证实。
适用性和可控性：复制模型应尽量考虑今后临床能应
用和便于控制其疾病的发展，以利于开展研究工作。 易行性和经济性：动物选择、复制方法、指标检测。
动物模型的评估：
其他因素容易控制，短时间内可复制大量的
动物模型 不足之处：诱发的与自然产生的在某些方面 有所不同。而且有些人类疾病不能用人工方 法诱发出来。
自发性动物模型：指不加任何人工诱发，在自然条件下 动物自然产生的疾病，或者由于基因突变的异常表现通 过遗传育种保留下来的动物疾病模型。其中包括近交系
的肿瘤疾病模型和突变系的遗传性疾病模型。突变系的
癌物作用过的器官、组织移植于同种或同种系裸鼠皮下进行 肿瘤的重复实验。
动物模型的分类动物模型的分类按产生原因分类自发性动物
动物模型的分类动物模型的分类一、按产生原因分类（一）自发性动物模型（Spontaneous Animal Models）是指how(event)"class="t_tag">实验动物未经任何有意识的人工处置，在自然情况下所发生的疾病。
包括突变系的遗传疾病和近交系的肿瘤疾病模型。
突变系的遗传疾病很多，可分为代谢性疾病、how(event)" class="t_tag">分子疾病和特种how(event)" class="t_tag">蛋白质合成异常性疾病。
如无胸腺裸鼠、肌肉萎缩症小鼠、肥胖症小鼠、癫痫大鼠、高血压大鼠、无脾小鼠和青光眼兔等。
它们为生物医学研究提供了许多有价值的动物模型。
近交系的肿瘤模型随how(event)"class="t_tag">实验动物种属、品系的不同，其肿瘤的发生类型和发病率有很大差异。
很多自发性动物模型在研究人类疾病时具有重要的价值，如自发性高血压大鼠，中国地鼠的自发性真性糖尿病，小鼠的各种自发性肿瘤，山羊的家族性甲状腺肿等。
利用这类动物疾病模型来研究人类疾病的最大优点，就是疾病的发生、发展与人类相应的疾病很相似，均是在自然条件下发生的疾病，其应用价值就很高，但是这类模型来源较困难，不可能大量应用。
由于诱发模型和自然产生的疾病模型是有一定差异的，如诱发的肿瘤和自发的肿瘤对药物的敏感性是不相同的，加之有些人类的疾病至今尚不能用人工的方法在动物身上诱发出来，因此，近年来十分重视对自发的动物疾病模型的开发，有的学者甚至对狗、猫的疾病进行大规模的普查，以发现自发性疾病的病例，然后通过遗传育种，将这种自发性疾病模型保持下来，并培育成具有特定遗传性状的突变系，以供研究。
近年来许多动物遗传病的模型就是通过这样的方法建立的。
在这方面小鼠和大鼠的各种自发性疾病模型开发和应用得最多。
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②移植性肿瘤的来源及常用动物 诱发性肿瘤、自发肿瘤、各种人和动物肿 瘤组织培养的细胞系。移植到免疫缺陷动物 或裸鼠身上。
常用肿瘤模型：鼻咽癌CNE-1、食管癌Eca-109、胃癌 MGC-803、肠癌CL-187和HCT、肝癌BAL-7402和 BAL-7721、肺癌A-549及ANIP-973、前列腺Pc-3m、 成骨肉瘤OS-732、乳腺癌B-37和MCF-7、卵巢癌 OVCAR-3、宫颈癌Hela等
1、实验动物自发肿瘤模型， ①概念 ：自发性肿瘤是动物没有经过人为的控 制和处理而自生的肿瘤 ②种类：
最多的动物是小鼠，国际公认的有250多个 。C3H系、 A 系、C57系。乳腺肿瘤、肺肿瘤、肝肿瘤、白血病等。大鼠品系 有130多种。有Wistar、SD、F344。自发瘤以肉瘤居多。大鼠 容易诱发肝癌。
3、高血压病动物模型 • 动脉收缩压和（或）舒张压升高，并常伴有 心、脑、肾和外周血管功能性或器质性改变 的全身性疾病。 • 常选用犬和大鼠，有时猪、猴、羊等。 • 实验性高血压通常以刺激中枢神经系统反 射性而成，或注射加压物质以及分次手术结 扎肾动脉，诱发肾原性高血压。
• SHR是良好的模型。 ①遗传因素占主要地位； ②在高血压早期无明显器质性改变； ③血压升高随年龄增加而加剧； ④紧张刺激和大量食盐等环境因素加重高 血压的发展； ⑤血压上升早期或高血压前期有高血流动 力学的特征； ⑥发生继发性心血管损害，出现心脑肾合 并症。 GH、SHRSP、STR等
常见模式生物：植物遗传研究的代表——拟南芥
点燃基因工程的先行者——大肠杆菌 食品与酒香催生了现代分子生物学——酵母
奠定现代发育生物学里程碑的海洋中刺客——海胆 现代生物医学中的新贵族——斑马鱼 丑陋的爪蟾变成发育生物学的王子——非洲爪蟾
讲述细胞凋亡故事的美丽公主——线虫 遗传学史上地位显赫国王——果蝇 诺贝尔奖的最大赢家——小鼠
生物性致癌因子：病毒。 人的EB病毒、乳头状瘤 病毒、乙型肝炎病毒等。
化学致癌物：氨基偶氮染料、芳香胺类、 植物毒素、亚硝胺类、真菌毒素、金属 致癌物等。
最近WHO公布的资料表明；现查明全 世界水体中，可检查出2221种化学物 质，其中饮用水中有害的有机污染物 765种，经鉴定确认其中致癌物有20 种，可致癌物23种，致突变物56种， 促癌剂18种。全世界每年有2.75亿人 因饮用污染的水而患病或死亡，在中 国，所患疾病的80%，死亡的1/3是饮 水不卫生造成的 。如果我们不再注意 对水资源的保护，就会出现：“水” 地 球上到处都有，但一滴也不能喝！
与生命科学研究前沿领域伴行
第五节 模 式 生 物
模式生物定义 观察基本生命现象，可将普遍原理推演到相关的生物 物种中， 对生物特征已有全面研究。
具有的共同特点： 其生理特征能够代表生物界的某一大类群； 容易获得并易于在实验室内饲养、繁殖；容 易进行实验操作，特别是遗传学分析；生命 结构都很简单。
药物法： 给动物注射垂体后叶素，可有典型心肌供血不全和心电 图改变。 电刺激法 ：用两支涂绝缘漆的不锈钢针，交替刺激右侧下丘脑。 所产生的缺血性心电图变化与人的心绞痛发作时相似。 外科手术：结扎左冠状动脉前降支
a
心电导联的变化 TTC染色梗死
c
a
b
c
d
e
f
HE染色心肌损伤的病理学改变
免疫荧光心肌组织中细胞的浸润
染色体端粒缩短与细胞衰老 端粒——端 粒 钟 学 说（telomere clock theory) •端粒（telomere)是染色体末端特殊结构。 人类端粒（TTAGGG)n n=250-15难题，即“癌症、特定遗传 病和衰老”。
肿瘤疾病动物模型及分类
4、 转基因动物在肿瘤研究中的应用
先进性：
A、可针对性地诱发特定组织及器官的肿瘤。 B、诱发的肿瘤为宿主自身的肿瘤。 C、具有恒定性与可遗传性。 D、通过插入标记基因，可掌握肿瘤转移过程的迁移途径及器 官选择性。
二、心血管疾病动物模型(Animal Models of Atheromatous) 1、动脉粥样硬化症动物模型 在动物饲料中加入过量的胆固醇和脂肪，其 主动脉及冠状动脉处逐渐形成粥样硬化斑块，并 出现高血脂症。 大鼠、小鼠、猪、犬、非人灵长类等动物有 一定自发率。
冷冻法复制角膜内皮损伤动物模型 MPTP 致帕金森病模型
MPTP 是一主要针对DA能神经元的 神经毒素,其毒性作用机制 主要通过抑制线粒体呼吸链复合体I的活性以及由此诱发的氧化 应激反应实现。这些因素均可加剧自由基的过度生 成,降低细胞 对自由基损伤的抵抗能力,最终导致 DA 能神 经元变性、死亡。
三、神经系统疾病动物模型 1、缺血性脑中风动物模型 （Ischemic stroke model ） 中风在世界范围内是与心血 管病和癌症并列的常见病。 每年我国有大约250万新发 脑中风的病例，死亡率为 1.2／1000 常选择的实验动物：长 爪沙鼠、大鼠、兔、犬、 非人灵长类等动物。
• 建立猴局灶缺血性脑中风模型： • a 成年雄性猕猴； • b用Laser Doppler Flowmetry测定即时局部脑 血流量； • c. 对脑无损伤的大脑中动脉闭塞手术； • d. 神经症状评判； • e. 神经图像检查
• 3、老年痴呆动物模型（Alzheimer disease model AD) 病理突出改变是基底前脑胆碱能细胞的 大量丧失和胆碱能神经功能下降。 SD雌性大鼠：侧脑室注射胆碱能毒剂损 伤基底前脑胆碱能神经。
四、 内分泌、营养代谢性疾病动物模型 糖尿病动物模型(Animal model of diabetes mellitus) 可选择犬、大鼠、兔等实验动物。猴 类的自发性糖尿病的临床特征与人类的十 分相似。
方法：
• ①注射致高血糖因子，如生长激素、胰高糖素、糖皮质激 素及儿茶酚胺类激素等； • ②引起胰岛β细胞的损伤。四氧嘧啶等可造成不可逆损伤。 天门冬素酶等引可逆性损伤； • ③生物及生物制品引起β细胞破坏，如鼠脑炎、心肌炎 (EMC)病毒M型变异可诱发若干品系的成年小鼠糖尿病； • ④手术切除胰腺的大部分或全部，并给予高糖饮食刺激， 引起继发性永久性糖尿病； • ⑤筛选遗传性及自发性糖尿病种群。
disease)
是指与人类各系统疾病相应的动物模型。 3、中医药动物模型 “辨证论治”独特理论体系。在实验动物身上复 制临床不同的征候，以不同的证型表现的一类 动物。
三、人类疾病动物模型的评估
没有一种动物模型能完全复制人类疾病真实情 况，动物毕竟不是人体的缩影。模型实验只是一 种间接性的研究，只可能在一个局部或几个方面 与人类疾病相似。动物模型实验结论的正确性只 是相对的，最终必须在人体身上得到验证。 动物模型的评估
二、按系统范围分类 1、疾病基本病理过程动物模型（animal model of
fundamently pathologic processes of disease)
是指致病因素在一定条件下作用动物后，所出 现的共同性的功能、代谢和形态结构某些改变的动 物模型。 2、各系统疾病动物模型（animal model of different system
选择比较： 小型猪：最佳选择 猴：理想的模型。 兔：常用 外源性胆固醇的吸收率达75％~90％。短期 内使主动脉斑块发生率达100％。血源性泡沫 细胞增多，病变分布与人的病变有差异。 大鼠： 食性与人相近，饲养方便。病理改变与人 早期相似，后期病变有差异，较易形成血栓。 小鼠：较少采用。
2、心肌缺血动物模型 电刺激法和药物注射法使动物心脏冠状动脉 发生痉挛性收缩，可造成人工急性心肌缺血动物 模型。犬、猪、兔和大鼠。
表 型 分 析
遗 传 学 分 析
表 型 分 析
实 用 性 分 析
第四节 常用人类疾病动物模型
一、肿瘤疾病动物模型(Animal Models of Tumor) 基本概念及特征：
肿瘤包括良性肿瘤及恶性肿瘤。恶性肿瘤是细胞失去 控制的异常增殖和对临近正常组织的侵犯及经血管、淋巴 管和体腔转移到身体其他部位。1、即原癌基因。2、抑制 肿瘤基因。 3、端粒和端粒酶
脑血流的减少程度和时间决定脑梗死的程度。大脑中动脉闭塞并持 续一小时，就会造成脑缺血核心区的神经元不可逆转性溃变。而其 周边的脑部神经元丧失诱发电位，但是细胞的离子通道却依然存在。
脑核磁共振图像显示脑梗死灶位置、大小
大脑中动脉起始部阻塞，正常大脑中动脉及其分支
• 2、Parkinson病动物模型（ Parkinson disease model PD) 与黑质-纹状体投射系统的多巴胺神经元 退行性变致神经递质多巴胺减少有关。多采用 化学法。 猴Parkinson模型 ：用N-甲基-4苯基-1， 2，3，6四氢吡啶 (MPTP)颈总动脉注射。
第三节 动物模型分类
一、按产生原因分类 1、自发性动物模型（Spontaneous Animal Models） 是指实验动物未经任何 有意识的人工处理，在自然 情况下所发生的疾病。
例如：癫痫长爪沙鼠，自发性疾病 小鼠山羊家族型甲状腺肿，牛免疫 缺陷病。
2、诱发性或实验性动物模型 （Experimental Animal Models） 实验性动物模型是指研究者通过使用物理的、 化学的和生物的致病因素作用于动物，造成动物 组织、器官或全身一定的损害，出现某些类似人 类疾病时的功能、代谢或形态结构方面的病变。
08年，西班牙国立癌症研究中心的科学家将端粒酶植入小白鼠的干细胞中， 小白鼠寿命延长50%。这种改良老鼠经过继续喂养，新DNA形态会进一 步加强。产生了“超级老鼠”，寿命更长，有抗癌能力。伊丽莎白· 布莱克 本、卡萝尔· 格雷德和杰克· 绍斯塔克，以表彰他们“发现端粒和端粒酶是 如何保护染色体的”， 2009年度诺贝尔生理学或医学奖。
模式动物与动物模型区别 基本生命现象，特殊 固有的， 创造的 基础研究， 应用研究 结构简单， 复杂
海胆 Echinoidea