Understanding mechanism(s)that regulate liver growth and function

了解调节肝脏生长和功能的机制

基本信息

批准号：
9511807
负责人：
Sayeepriyadarshini Anakk
金额：
$ 34.62万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9511807
关键词：
Address Affect Anabolism Biochemical Biological Biological Assay Catalytic Domain Cell Cycle Cell Cycle Progression Cell physiology Cells ChIP-seq Chromosome Pairing DNA biosynthesis Data Deoxyribonucleotides Diploidy Drug Metabolic Detoxication Enzymes Exhibits Gene Expression Genes Genetic Transcription Goals Growth Hepatic Hepatocyte Individual Laboratories Ligands Link Liver Liver Dysfunction Liver Failure Liver Regeneration Liver diseases Luciferases Mediating Metabolic Microscopy Mus Natural regeneration Nuclear Receptors Nutrient Partial Hepatectomy Pathway interactions Pharmaceutical Preparations Pharmacology Study Ploidies Poison Polyploidy Process RRM2 gene Receptor Activation Regenerative response Regulation Ribonucleotide Reductase Ribonucleotide Reductase Subunit Role Site Stress Testing Toxin Transplantation Wild Type Mouse Xenobiotics base constitutive androstane receptor design experimental study gene synthesis histological studies knock-down liver cell proliferation loss of function new therapeutic target novel novel strategies overexpression promoter receptor regenerative response sensor small hairpin RNA transcriptome transcriptome sequencing

项目摘要

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.

项目概要肝脏处理多种分子，包括营养物、毒素和药物。常规排毒肝脏中这些化合物的主要由核受体组成性雄激素协调受体（CAR）。有趣的是，CAR 通过其配体 TCPOBOP (TC) 激活，同时增加肝脏的代谢潜力，诱导肝脏 DNA 复制和随后的肝脏生长。这促进这种 CAR 依赖性肝脏生长的机制尚不完全清楚。没想到，我们发现 CAR 激活可以通过诱导几种基因的表达来增加 dNTP 的从头合成参与此过程的酶包括核糖核苷酸还原酶 M2 (RRM2)。 RRM2 是催化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 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 合成对于促进肝脏生长是否必要且充分，以及 (2) 如果 CAR-RRM2 轴促进肝脏的多倍体和再生。总体而言，该项目不仅揭示 CAR 在调节细胞 dNTP 水平中的基本作用，同时还发现了新的 CAR 实现其促有丝分裂作用的机制。