Expression and regulation of human genes central to drug disposition in the brain

对人类基因调控的研究本身就很困难。很难或不可能进入健康或患病个体的许多身体组织来检查协调基因功能（或功能障碍）。对于大脑来说尤其如此，因为活体人体组织是不可用的。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，大鼠和小鼠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效地反映在人类身上发生的情况。为了加深我们对人类大脑基因的理解，我们需要开发更忠实地再现人类环境的模型，这种环境既可以被操纵，也可以被仔细检查，比如本应用中描述的新型“人性化”小鼠模型。该应用程序处理控制属于人类细胞色素P450 3A （CYP3A）亚家族和药物转运体MDR1的酶的基因。这些基因存在于肝脏、肠道、肺和大脑等几个组织中。它们构成了药物、环境污染物和一些致癌化学物质等外来化学物质的主要处置途径。此外，它们还参与分解一些重要的内部产生的物质，如类固醇激素。我们推测，大脑中CYP3A酶和MDR1形成的改变会对许多重要药物的作用产生巨大影响，并可能影响大脑对激素（如性类固醇）的行为反应方式。此外，这项工作将为设计和开发大量作用于中枢神经系统的药物提供新的有用信息。

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). This is particularly true for the brain, where live human tissue is unavailable. 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 in brain 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 'humanized' mouse models described in this application. This application deals with the genes that control enzymes belonging to the human cytochrome P450 3A (CYP3A) subfamily and the drug transporter MDR1. These genes are present in several tissues including liver, gut, lung and brain. 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. We postulate that altered formation of CYP3A enzymes and MDR1 in brain can have a dramatic impact on the action of many important drugs and may affect the way the brain responds in a behavioral sense to hormones, such as sex steroids. In addition, this work will provide a new and useful information relevant to the design and development of the plethora of drugs that act on the central nervous system.