Expression, Regulation and Function of the SULT1C Carcinogen-Activating Enzymes

SULT1C 致癌物激活酶的表达、调节和功能

基本信息

批准号：
8630309
负责人：
Melissa A Runge-Morris
金额：
$ 41.47万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-08 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630309
关键词：
2-Acetylaminofluorene Address Adult Aromatic Amines Aryl Hydrocarbon Receptor Bile Acids Carcinogens Cell Culture Techniques Cell Line Cell model Cells Chemicals Cholesterol Clinical Cytosol DNA Damage Development Diabetes Mellitus Disease Disease susceptibility Environment Environmental Carcinogens Environmental Exposure Enzymes Epithelial Cells Family Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Heart Heart Diseases Hepatic Hepatocyte Histocompatibility Testing Homeostasis Hormones Human Human Development Human Genome Individual Infant Intestines Kidney Kinetics Knowledge Large Intestine Libraries Life Light Lipids Liver Malignant Neoplasms Messenger RNA Metabolic Metabolism Modeling Molecular Molecular Models Nuclear Nucleic Acid Regulatory Sequences Organ Orphan Pathology Pattern Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacologic Substance Physiological Physiology Plasmids Play Positioning Attribute Predisposition Process Property Proteins RNA Splicing Regulation Relative (related person)Reporter Research Rifampin Role Safety Sampling Signal Pathway Signal Transduction Site Small Intestines Staging Sterols Stimulus Stomach Structure Testing Tetrachlorodibenzodioxin Time Tissues Toxic effect Transcript Transcription Factor 3 Tubular formation Variant Vitamin D3 Receptor Work Xenobiotics detoxication dihydroxy-vitamin D3 drug efficacy drug metabolism environmental chemical enzyme substrate fetal induced pluripotent stem cell inhibitor/antagonist kidney cell mRNA Expression molecular modeling novel pharmacophore postnatal pregnane X receptor prenatal protein expression public health relevance receptor response rosiglitazone sulfation sulfotransferase transcription factor treatment effect

项目摘要

DESCRIPTION (provided by applicant): A major clinical challenge is the realization that common diseases such as diabetes, atherosclerotic heart disease, and even some cancers that used to be considered as adult-onset pathologies may actually have their origins during early periods of human development. The cytosolic sulfotransferases (SULTs) catalyze the conjugation of pharmaceuticals, environmental chemicals, hormones, cholesterol, and bile acids. Our long term goal is to understand how differences in SULT1C expression during the stages of development might impact drug efficacy and safety as well as susceptibility to environmental carcinogens and modulators of metabolic processes. Our short-term goals are to determine the expression pattern and regulators of SULT1C expression and to elucidate substrates and inhibitors of SULT1C metabolism. Unlike other xenobiotic- metabolizing enzymes, SULT1Cs are predominantly expressed during fetal life and are known to bioactivate xenobiotic molecules to toxic and carcinogenic intermediates. However, the role(s) of the SULT1C enzymes in endogenous metabolism and physiology are, as yet, uncharacterized. Our discovery that SULT1C genes are regulated by lipid- and xenobiotic-sensing transcription factors defines an unforeseen role for SULT1C enzymes at the heart of human development and metabolic signaling while also indicating that SULT1C enzymes operate at the interface of the physiological and xenobiotic environments. The hypothesis is that (1) the human SULT1C genes are differentially expressed in liver, kidney, stomach, and intestine and during development, (2) expression of these SULTs is differentially regulated by nuclear signaling mechanisms that include the farnesoid X receptor (FXR), the liver X receptor (LXR), the vitamin D receptor (VDR), peroxisome proliferator-activated receptor ? (PPAR?), and the xenobiotic-sensing receptors pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR), and (3) certain sterols and/or bile acids are endogenous substrates for the SULT1C enzymes. To test this hypothesis, the four specific aims of this proposal are to, (1) Determine the expression of human SULT1C2, SULT1C3, and SULT1C4 in fetal, infant, and adult tissue from liver, kidney, stomach, and intestine, (2) Define the mechanisms that control transcription of human SULT1C2, SULT1C3, and SULT1C4 in cellular models of liver, kidney, and intestine, with emphasis on regulation by lipid- and xenobiotic-sensing transcription factors, (3) Define the mechanism(s) that regulate SULT1C2 transcription during hepatic differentiation, and (4) Identify the structure-function activity and inhibition relationships of the human SULT1C enzymes. This project will shed new light on human SULT1C gene expression, regulation, and function. It is essential to obtain this understanding since the SULT1C enzymes likely play important physiological roles during development and, due to their distinct abilities to bioactivat toxic and carcinogenic compounds, are primed to promote disease susceptibility during critical windows of vulnerability.

描述（由申请人提供）：一个主要的临床挑战是认识到糖尿病、动脉粥样硬化性心脏病等常见疾病，甚至一些过去被认为是成人发病的癌症实际上可能起源于人类发育的早期阶段。胞质磺基转移酶 (SULT) 催化药物、环境化学物质、激素、胆固醇和胆汁酸的结合。我们的长期目标是了解开发阶段 SULT1C 表达的差异如何影响药物的功效和安全性以及对环境致癌物和代谢过程调节剂的敏感性。我们的短期目标是确定 SULT1C 表达的表达模式和调节因子，并阐明 SULT1C 代谢的底物和抑制剂。与其他异生物质代谢酶不同，SULT1C 主要在胎儿期表达，并且已知可将异生物质分子生物激活为有毒和致癌中间体。然而，SULT1C 酶在内源代谢和生理学中的作用尚未得到表征。我们发现 SULT1C 基因受脂质和外来生物感应转录因子调节，这一发现定义了 SULT1C 酶在人类发育和代谢信号传导核心中不可预见的作用，同时也表明 SULT1C 酶在生理和外来生物环境的界面上发挥作用。假设是 (1) 人类 SULT1C 基因在肝脏、肾脏、胃和肠道以及发育过程中存在差异表达，(2) 这些 SULT 的表达受到包括法尼醇 X 受体 (FXR) 在内的核信号传导机制的差异调节、肝脏X受体（LXR）、维生素D受体（VDR）、过氧化物酶体增殖物激活受体？ (PPAR？)，以及异生物质感应受体孕烷X受体(PXR)和芳烃受体(AhR)，以及(3)某些甾醇和/或胆汁酸是SULT1C酶的内源性底物。为了检验这一假设，该提案的四个具体目标是，(1) 确定人类 SULT1C2、SULT1C3 和 SULT1C4 在胎儿、婴儿和成人肝脏、肾脏、胃和肠组织中的表达，(2)定义在肝、肾和肠细胞模型中控制人 SULT1C2、SULT1C3 和 SULT1C4 转录的机制，重点是脂质和异生物质感应转录因子的调节， (3) 定义在肝分化过程中调节 SULT1C2 转录的机制，以及 (4) 确定人类 SULT1C 酶的结构-功能活性和抑制关系。该项目将为人类 SULT1C 基因表达、调控和功能提供新的线索。了解这一点至关重要，因为 SULT1C 酶可能在发育过程中发挥重要的生理作用，并且由于其生物激活有毒和致癌化合物的独特能力，因此在关键的脆弱窗口期会促进疾病易感性。