Cytochrome P450 CYP3A Regulation in Humanized Transgenic Mice

研究人类基因的调控本身就很困难。无论是健康的还是患病的个体，都很难或不可能获得许多身体组织来检查协调的基因功能(或功能障碍)。出于这个原因，我们往往对大鼠和小鼠等物种的基因功能有了更好的了解，这些物种是生物医学研究最常见的动物环境。然而，在动物身上的发现往往不能有意义地反映在人类身上发生的事情。为了提高我们对人类基因的理解，我们需要开发更真实地再现人类环境中人类情况的模型，这种环境既适合操作，也适合近距离检查，例如本申请中描述的新颖的人性化小鼠模型。这项应用涉及控制肝酶的调节基因，属于人类细胞色素P450 3A(CYP3A)亚家族。这些酶存在于几个组织中，包括肝脏、肠道、肺和乳房。它们构成了药物、环境污染物和一些致癌化学品等外来化学品的主要处置途径。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。细胞色素P3A酶的形成变化会对许多重要药物的作用产生重大影响，并可能导致某些形式的癌症。在这个项目中，我们将把人类所有四种CYP3A酶的基因植入小鼠体内。我们希望这些“人性化”的小鼠模型能够有效地在一个方便的动物模型中研究人类的情况，并允许进行详细的研究。了解细胞色素P3A酶的形成机制对于药物和类固醇代谢(在健康和疾病状态下)、肝脏疾病和胎儿药理学领域具有特别重要的意义。此外，这些模型将为药物开发提供一个新的有用工具。

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.