Establishment of a Bernard-Soulier syndrome model in zebrafish.
Establishment of a Bernard-Soulier syndrome model in zebrafish.
复制标题
斑马鱼Bernard-Soulier综合征模型的建立
DOI：
10.3324/haematol.2021.278893
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发表时间：
2022-07-01
期刊：
影响因子：
10.1
通讯作者：
Zhang, Yiyue
中科院分区：
文献类型：
--
作者：
Lin, Qing;Zhou, Riyang;Meng, Panpan;Wu, Liangliang;Yang, Lian;Liu, Wenyu;Wu, Jiaye;Cheng, Yuhuan;Shi, Linjuan;Zhang, Yiyue
血小板在血栓形成和止血中起着重要作用。异常止血可引起自发性或严重的创伤后出血。Bernard-Soulier综合征（BSS）是一种罕见的遗传性出血性疾病，由GPIb-IX-V复合物的完全定量缺陷引起。GP 9的多个突变导致BSS的临床表现。了解GP 9在血小板生成中的作用及其机制，建立合适的BSS动物模型，对于了解BSS的发病机制和提高其治疗水平具有重要意义。在这里，通过使用CRISPR-Cas9技术，我们创建了斑马鱼gp 9 SMU 15突变体来模拟人类BSS。斑马鱼gp 9的破坏导致血小板减少和明显的出血倾向，以及祖细胞的异常扩增。由于GP 9在血小板生成中的作用从斑马鱼到哺乳动物都是高度保守的，因此gp 9 SMU 15斑马鱼可以用作BSS动物模型。利用BSS模型，我们通过体内功能测定验证了临床GP 9突变，并测试了临床药物增加血小板的能力。因此，遗传性BSS斑马鱼模型可能有利于在体内验证患者来源的GP 9变异的不确定的意义，并为BSS的潜在治疗策略的发展。
Platelets play an essential role in thrombosis and hemostasis. Abnormal hemostasis can cause spontaneous or severe post-traumatic bleeding. Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder caused by a complete quantitative deficiency in the GPIb-IX-V complex. Multiple mutations in GP9 lead to the clinical manifestations of BSS. Understanding the roles and underlying mechanisms of GP9 in thrombopoiesis and establishing a proper animal model of BSS would be valuable to understand the disease pathogenesis and to improve its medical management. Here, by using CRISPR-Cas9 technology, we created a zebrafish gp9SMU15 mutant to model human BSS. Disruption of zebrafish gp9 led to thrombocytopenia and a pronounced bleeding tendency, as well as an abnormal expansion of progenitor cells. The gp9SMU15 zebrafish can be used as a BSS animal model as the roles of GP9 in thrombocytopoiesis are highly conserved from zebrafish to mammals. Utilizing the BSS model, we verified the clinical GP9 mutations by in vivo functional assay and tested clinical drugs for their ability to increase platelets. Thus, the inherited BSS zebrafish model could be of benefit for in vivo verification of patient-derived GP9 variants of uncertain significance and for the development of potential therapeutic strategies for BSS.
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DOI：
10.1083/jcb.201304054
发表时间：
2013-06-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Machlus KR;Italiano JE Jr
通讯作者：
Italiano JE Jr
影响因子：
3.7
作者：
Kim S;Carrillo M;Kulkarni V;Jagadeeswaran P
通讯作者：
Jagadeeswaran P
影响因子：
64.5
作者：
Kim AR;Ulirsch JC;Wilmes S;Unal E;Moraga I;Karakukcu M;Yuan D;Kazerounian S;Abdulhay NJ;King DS;Gupta N;Gabriel SB;Lander ES;Patiroglu T;Ozcan A;Ozdemir MA;Garcia KC;Piehler J;Gazda HT;Klein DE;Sankaran VG
通讯作者：
Sankaran VG
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
20.3
作者：
Lordier, Larissa;Jalil, Abdelali;Chang, Yunhua
通讯作者：
Chang, Yunhua