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.的新型基因敲除小鼠品系的产生

Generation of New Knock-Out Mouse Strains of .

作者信息

Antonopoulou Georgia, Magkrioti Christiana, Chatzidaki Ismini, Nastos Dimitris, Grammenoudi Sofia, Bozonelos Konstantinos, Aidinis Vassilis

机构信息

Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece.

出版信息

Int J Mol Sci. 2025 Mar 20;26(6):2811. doi: 10.3390/ijms26062811.

DOI:10.3390/ijms26062811
PMID:40141453
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11942715/
Abstract

The lysophosphatidic acid receptor 1 (LPAR1) is one of the six cognate G protein-coupled receptors of the bioactive, growth factor-like phospholipid lysophosphatidic acid (LPA). LPAR1 is widely expressed in different cell types and mediates many LPA effects. LPAR1 has been implicated in several chronic inflammatory diseases, and especially pulmonary fibrosis, where it has been established as a promising therapeutic target. Herein, we present the generation of several mouse strains through genetic recombination. These strains include an initial versatile strain (tm1a) from which three other strains derive: an reporter knockout strain (tm1b) where LacZ has replaced exon 3 of ; a "floxed" strain (tm1c), where exon 3 is flanked by two loxP sites allowing conditional, cell-specific inactivation; and a complete KO strain of (tm1d), where exon 3 has been deleted. The generated strains are novel genetic tools, that can have various applications in studying LPA-LPAR1 signaling and its role in normal physiology and disease.

摘要

溶血磷脂酸受体1(LPAR1)是生物活性、生长因子样磷脂溶血磷脂酸(LPA)的六种同源G蛋白偶联受体之一。LPAR1在不同细胞类型中广泛表达,并介导许多LPA效应。LPAR1与多种慢性炎症性疾病有关,尤其是肺纤维化,在肺纤维化中它已被确立为一个有前景的治疗靶点。在此,我们通过基因重组展示了几种小鼠品系的产生。这些品系包括一个初始通用品系(tm1a),其他三个品系由此衍生而来:一个报告基因敲除品系(tm1b),其中LacZ取代了[具体基因]的外显子3;一个“floxed”品系(tm1c),其中外显子3两侧有两个loxP位点,允许条件性、细胞特异性失活;以及一个[具体基因]的完全敲除品系(tm1d),其中外显子3已被删除。所产生的品系是新型遗传工具,可在研究LPA-LPAR1信号传导及其在正常生理学和疾病中的作用方面有多种应用。

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本文引用的文献

1
Efficacy and Safety of Admilparant, an LPA Antagonist, in Pulmonary Fibrosis: A Phase 2 Randomized Clinical Trial.LPA拮抗剂Admilparant在肺纤维化中的疗效与安全性:一项2期随机临床试验
Am J Respir Crit Care Med. 2025 Feb;211(2):230-238. doi: 10.1164/rccm.202405-0977OC.
2
Pharmacokinetics of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulator of Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers.法匹拉帕仑的药代动力学:一种小分子、LPA1 受体的选择性负变构调节剂,以及在健康志愿者中食物的影响。
Clin Pharmacol Drug Dev. 2024 Jul;13(7):819-827. doi: 10.1002/cpdd.1417. Epub 2024 May 17.
3
Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression.
溶血磷脂酸受体信号在人乳腺癌肿瘤微环境中引发受体依赖性的肿瘤进展效应。
Int J Mol Sci. 2023 Jun 6;24(12):9812. doi: 10.3390/ijms24129812.
4
Lysophosphatidic Acid Is a Proinflammatory Stimulus of Renal Tubular Epithelial Cells.溶血磷脂酸是肾管状上皮细胞的促炎刺激物。
Int J Mol Sci. 2022 Jul 5;23(13):7452. doi: 10.3390/ijms23137452.
5
Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model.溶血磷脂酸受体 1 的消融可减轻肥厚型心肌病小鼠模型的心肌肥厚。
Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2204174119. doi: 10.1073/pnas.2204174119. Epub 2022 Jul 5.
6
LPA antagonist BMS-986020 changes collagen dynamics and exerts antifibrotic effects in vitro and in patients with idiopathic pulmonary fibrosis.LPA 拮抗剂 BMS-986020 改变胶原动力学并在特发性肺纤维化患者的体外和体内发挥抗纤维化作用。
Respir Res. 2022 Mar 18;23(1):61. doi: 10.1186/s12931-022-01980-4.
7
Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate.溶血磷脂酸和鞘氨醇 1-磷酸对脂质 GPCR 的差异化激活机制。
Nat Commun. 2022 Feb 8;13(1):731. doi: 10.1038/s41467-022-28417-2.
8
Generation of an Lpar1-EGFP Fusion Knock-in Transgenic Mouse Line.生成 Lpar1-EGFP 融合基因敲入转基因小鼠品系。
Cell Biochem Biophys. 2021 Sep;79(3):619-627. doi: 10.1007/s12013-021-01033-5. Epub 2021 Oct 15.
9
Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance.神经嵴样干细胞转录组分析鉴定 LPAR1 在黑色素瘤进展和治疗耐药中的作用。
Cancer Res. 2021 Oct 15;81(20):5230-5241. doi: 10.1158/0008-5472.CAN-20-1496. Epub 2021 Aug 30.
10
Platelet-derived lysophosphatidic acid mediated LPAR1 activation as a therapeutic target for osteosarcoma metastasis.血小板衍生的溶血磷脂酸介导的 LPAR1 激活作为骨肉瘤转移的治疗靶点。
Oncogene. 2021 Sep;40(36):5548-5558. doi: 10.1038/s41388-021-01956-6. Epub 2021 Jul 23.