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ALTERED INTRACELLULAR PH AS A MECHANISM OF TERATOGENESIS

细胞内相位改变是致畸机制

基本信息

批准号：
3316500
负责人：
WILLIAM J SCOTT
金额：
$ 7.96万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-04-01 至 1989-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3316500
关键词：
acetazolamide acid base balance alcohols autoradiography carbon dioxide carbonate dehydratase carbonic anhydrase inhibitors congenital skeletal disorder gestational age histogenesis hypercapnia laboratory mouse prenatal growth disorder radiotracer teratogens

项目摘要

Acetazolamide induces a unique and characteristic limb deformity in the offspring of pregnant rodents. The teratogenic mechanism of action is thought to be inhibition of carbonic anhydrase. One after effect of carbonic anhydrase inhibition is raised arterial and tissue carbon dioxide content and we have now demonstrated that maternal carbon dioxide inhalation leads to the same unique forelimb deformity substantiating the idea that carbonic anhydrase inhibition is the mechanism of acetazolamide teratogenesis. This application describes experiments which will attempt to uncover the mechanism by which C02 perturbs development. We hypothesize that C02 lowers intracellular pH (pHi) which subsequently leads to decreased proliferative rate thereby leading to the limb reduction deformity. We will measure pHi in the developing limb bud after teratogen treatment and attempt to correlate any changes with teratologic outcome and proliferative rate. The ability of limb bud cells to respond to internal pH changes will be documented and manipulation of this process will be correlated with teratologic outcome. We believe that reducing the intracellular pH of embryonic cells may be a general mechanism of teratogenesis and intend to study one human teratogen, alcohol, which could conceivably act through this mechanism.

乙酰唑胺可引起一种独特的肢体畸形怀孕的啮齿动物的后代。其致畸作用机制是被认为是对碳酸酐酶的抑制。一个后遗症碳酸酐酶抑制会增加动脉和组织的二氧化碳现在我们已经证明了母体的二氧化碳吸入会导致同样独特的前肢畸形，证实认为碳酸酐酶抑制是乙酰唑胺的作用机制畸形症。这个应用程序描述了将试图揭示二氧化碳干扰发育的机制。我们假设二氧化碳降低细胞内pH(Phi)，从而导致降低增殖率，从而导致肢体复位畸形。我们将测量发育中的肢芽在致畸治疗后的phi和尝试将任何变化与畸胎结局和增生性疾病相关联费率。肢芽细胞对内部pH变化的反应能力将该流程的操作将与以下内容相关畸形结局。我们认为，降低胚胎细胞的细胞内pH可能是一种致畸的一般机制，并打算研究一种人类致畸因子，酒精，它可以通过这种机制发挥作用。