Cytochrome P450 CYP3A Regulation in Humanized Transgenic Mice

人源化转基因小鼠中细胞色素 P450 CYP3A 的调节

• 批准号: nhmrc : 211117
• 负责人: A/Pr Graham Robertson
• 金额: $ 25.14万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2002
• 资助国家: 澳大利亚
• 起止时间: 2002-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/cytochrome-p450-cyp3a-transgenic-mice/99678
• 关键词: Cytochrome; P450; CYP3A; Regulation; Humanized

The study of the regulation of human genes is inherently difficult. It is difficult or impossible to gain access to many body tissues in either healthy or sick individuals to examine coordinated gene function (or dysfunction). For this reason, it is often the case that we have a much better understanding of gene function in species such as rats and mice, the most common animal environments for biomedical research. However, findings in animals often fail to meaningfully mirror what occurs in man. To progress our understanding of human genes we need to develop models that more faithfully reproduce the human situation in an environment that is amenable to both manipulation and close examination, such as the novel 'humanised' mouse models described in this application. This application deals with the regulation genes that control liver enzymes belonging to the human cytochrome P450 3A (CYP3A) subfamily. These enzymes are present in several tissues including liver, gut, lung and breast. They form the main disposal pathway for foreign chemicals such as drugs, environmental pollutants and some cancer causing chemicals. In addition they are involved in the breakdown of several important internally produced substances, such as steroid hormones. Altered formation of CYP3A enzymes can have a dramatic impact on the action of many important drugs and may predispose to some forms of cancer. In this project, we will insert the genes for all four human CYP3A enzymes into mice. We expect that these 'humanised' mouse models will effectively enable the human situation to be studied in a convenient animal model and allow detailed studies to be performed. A knowledge of the mechanisms involved in CYP3A enzyme formation is of particular importance to the fields of drug and steroid metabolism (both in health and in disease states), liver diseases and foetal pharmacology. In addition, these models will provide a new and useful tool for drug development.

研究人类基因的调节本来就很困难。很难或不可能获得健康或患病个体的许多身体组织来检查协调的基因功能（或功能障碍）。由于这个原因，通常情况下，我们对大鼠和小鼠等物种的基因功能有了更好的了解，这是生物医学研究中最常见的动物环境。然而，在动物身上的发现往往不能有意义地反映出在人类身上发生的情况。为了进一步了解人类基因，我们需要开发出在一个既适合操作又适合仔细检查的环境中更忠实地再现人类情况的模型，例如本申请中描述的新型“人源化”小鼠模型。本申请涉及控制属于人细胞色素P450 3A（CYP3A）亚家族的肝酶的调节基因。这些酶存在于几种组织中，包括肝、肠、肺和乳腺。它们是处理外来化学品，如药物、环境污染物和某些致癌化学品的主要途径。此外，它们还参与分解几种重要的内部产生的物质，如类固醇激素。CYP3A酶的改变可能对许多重要药物的作用产生巨大影响，并可能使某些形式的癌症易感。在这个项目中，我们将把所有四种人类CYP3A酶的基因插入小鼠体内。我们希望这些“人源化”小鼠模型将有效地使人类的情况进行研究，在一个方便的动物模型，并允许进行详细的研究。了解CYP3A酶形成的机制对药物和类固醇代谢（健康和疾病状态）、肝脏疾病和胎儿药理学领域特别重要。此外，这些模型将为药物开发提供新的有用工具。