Understanding mechanism(s)that regulate liver growth and function

项目摘要 肝脏处理广泛的分子，包括营养物质，毒素和药物。常规解毒 这些化合物在肝脏中的作用主要是由核受体组成型雄激素 受体（CAR）。有趣的是，CAR通过其配体TCPOBOP（TC）的活化，沿着增加CAR的浓度， 肝脏的代谢潜力，诱导肝DNA复制和随后的肝脏生长。的 促进这种CAR依赖性肝脏生长的机制尚未完全理解。出乎意料的是，我们 发现CAR激活可以通过诱导几种dNTP的表达来增加从头dNTP合成， 参与该过程的酶包括核糖核苷酸还原酶M2（RRM 2）。RRM 2是催化剂 核糖核苷酸还原酶是负责dNTP生物合成的限速酶。 重要的是，我们发现RRM 2的诱导和随后的dNTP浓度的增加是通过诱导RRM 2和dNTP浓度的增加来实现的。 在Car-/-小鼠中完全不存在。这些发现表明，通过增加dNTP合成，CAR激活 可以提供适合DNA合成和增殖的细胞环境。在本提案中，我们将 确定（1）CAR介导的dNTP合成是否是促进肝脏生长所必需和充分的，和（2） 如果CAR-RRM 2轴促进肝脏中的多倍体和再生。总的来说，该项目不仅 揭示CAR在调节细胞dNTP水平中的基本作用， CAR实现其促有丝分裂作用的机制。

Project Summary The liver processes a broad range of molecules including nutrients, toxins, and drugs. Routine detoxification of these compounds in the liver is primarily orchestrated by the nuclear receptor Constitutive Androstance Receptor (CAR). Interestingly, CAR activation by its ligand TCPOBOP (TC), along with increasing the metabolic potential of the liver, induces hepatic DNA replication and subsequent liver growth. The mechanisms that facilitate this CAR-dependent liver growth are not fully understood. Unexpectedly, we discovered that CAR activation can increase de novo dNTP synthesis by inducing the expression of several enzymes involved in this process including Ribonucleotide Reductase M2 (RRM2). RRM2 is the catalytic subunit of Ribonucleotide Reductase, the rate-limiting enzyme responsible for dNTP biosynthesis. Importantly, we found that induction of RRM2 and subsequent increases in the dNTP concentrations were completely absent in Car-/- mice. These findings indicate that by increasing dNTP synthesis, CAR activation may afford a cellular milieu that is amenable for DNA synthesis and proliferation. In this proposal, we will determine (1) if CAR-mediated dNTP synthesis is necessary and sufficient to promote liver growth, and (2) if CAR-RRM2 axis promotes polyploidy and regeneration in the liver. Overall, this project will not only uncover the fundamental role for CAR in regulating cellular dNTP levels but also identify novel mechanism(s) by which CAR achieves its mitogenic effects.