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一个小鼠模型用于快速和双项评估假设的WNT/β-catenin信号抑制剂
Janson Tse1, Ryan O'Keefe1,2, Angela Rigopolous2,3
1Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
Biomedicines
|October 28, 2023
概括
一种新的WNT/β-catenin抑制剂测定使用小鼠胚胎来评估药物的疗效. 这种方法拯救了Apc突变小鼠的胚胎死亡率,为药物开发提供了一个敏感的体内模型.
科学领域:
- 发展生物学 发展生物学
- 癌症生物学 癌症生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- WNT/β-catenin通路对于胚胎发生和组织平衡至关重要.
- 这种途径的突变,特别是APC基因的突变,驱动许多癌症,包括结直肠癌.
- 缺乏特定的体内试验阻碍了WNT/β-catenin抑制剂的临床开发.
研究的目的:
- 开发一种简单,敏感的体内测试方法,用于评估WNT/β-catenin抑制剂化合物.
- 利用胚胎发育作为WNT/β-catenin通路调节的读取结果.
- 克服当前测试的局限性,从毒性中区分目标效应.
主要方法:
- 将候选化合物给孕期,表型正常的Apc小鼠.
- 在APC突变概念中拯救子宫内死亡的评估作为二进制结果.
- 利用天生的 Apc conceptus 的现型可塑性来改进测试.
主要成果:
- 证明了一种简单的体内试验,对WNT/β-catenin对抗剂具有二元结果.
- 成功救出 Apc 突变概念的子宫内死亡.
- 为药物评估建立了一个明确而敏感的哺乳动物体内模型.
结论:
- 开发的试验适用于评估WNT/β-catenin对抗剂的疗效和生物可用性.
- 胚胎发育期间内源性WNT/β-catenin信号提供了一个强大的模型系统.
- 这种测定有助于未来的 WNT 途径抑制剂的剂量发现和交叉化合物比较.
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