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人源化ACE2小鼠助力新型冠状病毒相关研究

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SARS-CoV-2通过棘突Spike蛋白 (S蛋白)与人类细胞表面的ACE2受体结合,从而进入细胞体内进行复制和感染,引起级联免疫反应和细胞因子风暴。血管紧张素转换酶 (ACE)2 也称为ACEH,是一种锌金属蛋白酶,属于1型跨膜蛋白,结构包括一个信号肽、一个跨膜结构域和一个含有HEXXH锌结合结构域的金属蛋白酶活性位点,可降解Ang I生成九肽Ang 1-9,降解Ang II生成七肽Ang 1-7。ACE2的编码基因位于X染色体,主要在胃肠道、心脏、肾脏、肺、睾丸和大脑中表达。人类ACE2与小鼠ACE2序列存在关键差异,可以感染人类的SARS-CoV-2不一定能感染小鼠,因此野生型小鼠不适合进行该病毒研究及疫苗开发。


集萃药康采用基因编辑技术自主研发ACE2人源化小鼠模型,模拟人体感染新冠病毒的临床表征。在C57BL/6JGpt背景鼠上做ACE2人源化修饰的策略主要有三种,将鼠ACE2全长序列或胞外区原位替换为相应的人源序列,在不影响小鼠生理情况下最大限度让人源化ACE2的表达与小鼠自身ACE2在生理状态下的表达情况相同;或通过人类细胞角蛋白18(Cytokeratin 18,K18)启动子调控启动子驱动hACE2在安全岛H11位点过表达,用于模拟人类重度COVID-19表型;以及在BALB/c和NCG背景鼠上将鼠的ACE2全长序列替换为相应的人源序列。


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集萃药康的小鼠ACE2模型优势

l内源性调控机制下的hACE2在嵌合和全长hACE2原位KI小鼠中的表达

lNCG-HuACE2-FL可在SARS-CoV-2感染之前通过免疫系统重建来模拟细胞因子风暴

l双背景hACE2小鼠模型

l库存及及时交货


策略方法


1.K18-HuACE2 (T037657)


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Strategy of K18-hACE2 H11 KI mice



2.HuACE2-Chimera (T037630)


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Strategy of chimeric hACE2 mice



3.C57BL/6-HuACE2-FL (T037659)


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Strategy of full-Length hACE2 in situ KI mice


4. BALB/c-HuACE2-FL(T037915)

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Strategy of full-Length hACE2 in situ KI mice



5. NCG-HuACE2-FL (T037766)

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Strategy of NCG-hACE2 KI Mice



参考文献


[1] Ma X et al., Nanoparticle Vaccines Based on the Receptor Binding Domain (RBD) and Heptad Repeat (HR) of SARS-CoV-2 Elicit Robust Protective Immune Responses, Immunity (2020), doi: https://doi.org/10.1016/j.immuni.2020.11.015.

[2] Zhang et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. Journal of Hematology & Oncology. 2020, 13:120.

[3] XU K et al., Co-infection of influenza A virus enhances SARS-CoV-2 infectivity. https://doi.org/10.1101/2020.10.14.335893

[4] Yu-Tian Pan et al., Study on β-Chitosan against the binding of SARS-CoV-2S_x0002_RBD/ACE2.  https://doi.org/10.1101/2020.07.31.229781.

[5] Wu YT. Compensation of ACE2 Function for Possible Clinical Management of SARS-CoV-2-Induced Acute Lung Injury. 2020. DOI: 10.1007/s12250-020-00205-6.

[6] Cabin Fan, et al. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection. 2020. MedRxiv.

[7] Wang et al. Chronic Activation of the Renin-Angiotensin System Induces Lung Fibrosis. Sci Rep, 2015, 5: 15561.

[8] Marshall et al. Angiotensin II and the Fibroproliferative Response to Acute Lung Injury. Am J Physiol Lung Cell Mol Physiol, 2004, 286 (1): 156-164.

[9] Kuba et al. Trilogy of ACE2: A Peptidase in the Renin-Angiotensin System, a SARS Receptor, and a Partner for Amino Acid Transporters. Pharmacol Ther, 2010, 128 (1): 119-128.

[10] Patel et al. Role of the ACE2/Angiotensin 1-7 Axis of the Renin–Angiotensin System in Heart Failure. Circ Res. 2016, 118 (8): 1313-1326.

[11] Imai et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature, 2005, 436:112-116.

[12] Kuba et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med, 2005, 11: 875-879.

[13] NetlandJ.et al. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 2008, 82(15): 7264-7275.