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

人类基因的表达和调节对于大脑中的药物分布至关重要

• 批准号: nhmrc : 352320
• 负责人: A/Pr Graham Robertson
• 金额: $ 22.63万
• 依托单位: The University of Sydney
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/expression-regulation-human-disposition-brain/97290
• 关键词: Expression; regulation; human; genes; central

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.

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）。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，这是生物医学研究中最常见的动物环境。然而，在动物中的发现往往不能有意义地反映发生在人身上的情况。为了促进我们对大脑中人类基因的理解，我们需要开发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）亚家族的酶和药物转运蛋白MDR 1的基因。这些基因存在于几种组织中，包括肝脏、肠道、肺和大脑。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。我们推测，改变CYP3A酶和MDR1在大脑中的形成可以对许多重要药物的作用产生巨大影响，并可能影响大脑在行为意义上对激素（如性类固醇）的反应方式。此外，这项工作将提供一个新的和有用的信息相关的设计和开发的过多的药物作用于中枢神经系统。