RORalpha and Hepatic Zonal Regulation

RORalpha 和肝区调节

• 批准号: 10179359
• 负责人: BRETT T SPEAR
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179359
• 关键词: Acetaminophen; Adult; Binding; Binding Sites; Biological Models; Biology; Carbon Tetrachloride; Cell Lineage; Cell Separation; Cell Surface Proteins; Central Vein; ChIP-seq; Conflict (Psychology); Data; Enhancers; Ethanol; Exhibits; Flow Cytometry; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Goals; Grant; Hepatic; Hepatocyte; Human; Individual; Knockout Mice; Link; Liver; Liver Regeneration; Lobule; Methods; Modeling; Mus; Mutate; Mutation; Natural regeneration; Nucleic Acid Regulatory Sequences; Orphan; Partial Hepatectomy; Pattern; Pharmacologic Substance; Play; Property; RORA gene; Regulation; Response Elements; Role; Signal Pathway; Site; Staggerer Mouse; Technology; Testing; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Tretinoin; alpha-Fetoproteins; beta catenin; fascinate; hepatocyte injury; hepatotoxin; improved; in vivo; insight; interest; liver function; liver injury; mouse model; novel; promoter; receptor; self-renewal; stem cell proliferation; stem cell self renewal; stem cells; transcription factor; transcriptome sequencing

The restricted expression of specific hepatic genes in pericentral or periportal regions of the adult liver, a phenomenon known as zonal regulation, is a fascinating aspect of liver biology. Elegant studies in the past 10 years have uncovered the role of the b-catenin signaling pathway in controlling zonal expression. Our recent studied using a novel mouse model system developed by us indicates that the retinoic acid-related orphan receptor alpha (RORa) also plays a role in controlling zonal gene expression. Furthermore, studies in other tissues have shown that RORa contributes to the differentiation and proliferation of stem cells, but this property has not been evaluated in the liver. We propose to use genetically modified mice and contemporary high- throughput genomic technologies to explore the role of RORa in the function and stem cell properties of pericentral hepatocytes. Since many hepatotoxins, including ethanol, and pharmaceuticals, such as acetaminophen, specifically damage pericentral hepatocytes, a better understanding of the mechanisms controlling gene expression in and the self-renewing properties of this subpopulation of hepatocytes will help develop strategies to reduce hepatocyte injury in humans.

肝特异性基因在门脉高压症中央或门脉周围区域的表达受限 成人肝脏，一种被称为区域调节的现象，是肝脏的一个迷人的方面 生物学在过去的10年里，优雅的研究已经揭示了b-连环蛋白的作用， 信号通路控制带状表达。我们最近研究了一本小说 我们开发的小鼠模型系统表明，维甲酸相关孤儿 受体α（RORa）也在控制区域基因表达中起作用。 此外，在其他组织中的研究表明，RORa有助于 干细胞的分化和增殖，但这种特性尚未在 肝脏我们建议使用转基因小鼠和当代高- 通量基因组技术，以探索RORa在功能和干细胞中的作用， 中央周围肝细胞的细胞特性。由于许多肝毒素，包括乙醇， 而药物，如对乙酰氨基酚， 肝细胞，更好地了解控制基因表达的机制， 这种肝细胞亚群的自我更新特性将有助于 减少人类肝细胞损伤的策略。

项目成果

Evolutionary Analysis of the Zinc Finger and Homeoboxes Family of Proteins Identifies Multiple Conserved Domains and a Common Early Chordate Ancestor

锌指和同源盒蛋白质家族的进化分析鉴定出多个保守结构域和共同的早期脊索动物祖先

• DOI: 10.1093/gbe/evaa039
• 发表时间: 2020
• 期刊: Genome Biology and Evolution
• 影响因子: 3.3
• 作者: Nail, Alexandra N;Smith, Jeramiah J;Peterson, Martha L;Spear, Brett T;Das, Sabyasachi
• 通讯作者: Das, Sabyasachi

Pericentral activity of alpha-fetoprotein enhancer 3 and glutamine synthetase upstream enhancer in the adult liver are regulated by β-catenin in mice.

• DOI: 10.1002/hep.25819
• 发表时间: 2012-11
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Clinkenbeard, Erica L.;Butler, James E.;Spear, Brett T.
• 通讯作者: Spear, Brett T.

Zinc fingers and homeoboxes 2 inhibits hepatocellular carcinoma cell proliferation and represses expression of Cyclins A and E.

• DOI: 10.1053/j.gastro.2012.02.049
• 发表时间: 2012-06
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Yue X;Zhang Z;Liang X;Gao L;Zhang X;Zhao D;Liu X;Ma H;Guo M;Spear BT;Gong Y;Ma C
• 通讯作者: Ma C

Zhx2 and Zbtb20: novel regulators of postnatal alpha-fetoprotein repression and their potential role in gene reactivation during liver cancer.

• DOI: 10.1016/j.semcancer.2011.01.001
• 发表时间: 2011-02
• 期刊: Seminars in cancer biology
• 影响因子: 14.5
• 作者: Peterson ML;Ma C;Spear BT
• 通讯作者: Spear BT

Alpha-fetoprotein related gene (ARG): a new member of the albumin gene family that is no longer functional in primates.

甲胎蛋白相关基因（ARG）：白蛋白基因家族的新成员，在灵长类动物中不再有功能。

• DOI: 10.1016/j.gene.2009.08.014
• 发表时间: 2010
• 期刊: Gene
• 影响因子: 3.5
• 作者: Naidu,Sathyabama;Peterson,MarthaL;Spear,BrettT
• 通讯作者: Spear,BrettT