Understanding mechanism(s)that regulate liver growth and function

项目摘要 肝脏处理一系列分子，包括营养物质、毒素和药物。常规戒毒 肝脏中的这些化合物主要是由核受体组成的雄激素调控的 受体(CAR)。有趣的是，CAR被其配体TCPOBOP(TC)激活，同时增加了 肝脏的代谢潜力，诱导肝脏DNA复制和随后的肝脏生长。这个 促进这种依赖于汽车的肝脏生长的机制尚不完全清楚。没想到，我们 发现CAR的激活可以通过诱导几个基因的表达来增加dNTP的从头合成 参与这一过程的酶包括核糖核苷酸还原酶M2(RRM2)。RRM2是催化剂 核糖核苷酸还原酶的亚基，负责dNTP生物合成的限速酶。 重要的是，我们发现RRM2的诱导和随后dNTP浓度的增加是 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 可能提供一个有利于DNA合成和增殖的细胞环境。在这项提案中，我们将 确定(1)CAR介导的dNTP合成是否必要且足以促进肝脏生长，以及(2) 如果CAR-RRM2轴促进肝脏的多倍体和再生。总体而言，这个项目不仅将 揭示CAR在调节细胞dNTP水平中的基本作用，同时发现新的 CAR实现其有丝分裂作用的机制(S)。

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.