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）：一个重大的临床挑战是认识到，糖尿病，动脉粥样硬化心脏病等常见疾病，甚至某些曾经被视为成年性病理学的癌症实际上也可能起源于人类发育的早期。胞质磺胺转移酶（Sults）催化了药物，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中SULT1C表达的差异如何影响药物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剂，并阐明Sult1c代谢的底物和抑制剂。与其他异种生物 - 代谢酶不同，SULT1C在胎儿寿命中主要表达，并且已知将生物活化的异生物生物分子分子毒性和致癌中介质物。然而，苏尔特1C酶在内源代谢和生理学中的作用尚未表征。我们发现，Sult1c基因受脂质和异种生物传感转录因子的调节，定义了SULT1C酶在人类发育和代谢信号的核心中的不可预见的作用，同时也表明SULT1C酶在物理和Xenobiotic环境的界面上运行。假设是（1）人类sult1c基因在肝，肾脏，胃和肠以及发育过程中差异表达，（2）这些苏尔特的表达受到核信号传导机制的差异调节，核信号传导机制包括法尼X受体（FXR），肝脏X受体（LXR），维生素D受体（VDRASIST），OXISIS，用户（vdr），用户？（PPAR？），以及异生元感应受体怀孕X受体（PXR）和芳基烃受体（AHR），以及（3）某些固醇和/或胆汁酸是Sult1c酶的内源性底物。为了检验该假设，该提案的四个具体目的是（1）确定人类Sult1c2，Sult1c3和Sult1c4在胎儿，婴儿和成人组织中的表达肠道强调脂质和异种生物传感转录因子的调节，（3）定义了调节肝分化过程中SULT1C2转录的机制，（4）确定人类SULT1C酶的结构函数活性和抑制关系。该项目将为人类Sult1c基因表达，调控和功能提供新的启示。必须获得这种理解，因为Sult1c酶在发育过程中可能起重要的生理作用，并且由于它们具有与生物活化有毒和致癌化合物的独特能力，因此在脆弱性的关键窗口中促进了疾病的敏感性。