Core--Mutant Mice

靶向P450基因破坏和/或过表达是该计划项目的一个重要组成部分，旨在提供P450酶在肾脏生理学或病理生理学中所起作用的分子描述。这些努力取得成功的关键是项目研究人员及时和不受限制地接触P450突变小鼠。动物核心（核心D）的总体目标是集中维持，育种和携带靶向基因破坏诱导的P450突变的小鼠品系的初始表征。预计拟议的集中化将大大节省时间和金钱，更有效地利用共同资源和专门知识，并提高总体生产率和重复性。具体而言，核心D将从项目2接收含有编码不同P450亚型的基因突变拷贝的育种对。交配、回交和育种技术将用于产生携带129 SvJ或C57 BL/6 J遗传背景的同源（+/+）和（-/-）基因型小鼠。核心D还将对携带突变P450基因型的小鼠进行初步形态学和功能评价。将这些常规任务集中在核心D中将消除不必要的和昂贵的重复，并将及时为项目1-4提供功能研究所需的突变动物。Cyp 4a 14（-/-）和4a 10（-/-）小鼠已经在129/SvJ背景下可用， Cyp 4a 14（-/-）也在同源C57 BL/6 J背景中。Cyp 4a 12无效突变体将在未来12-15个月内上市。Cyp 2c 44（-/-）小鼠将在未来2-3年内开发，Cyp 4a 12和2c 44转基因小鼠将在3-4年内开发。

Targeted P450-gene disruption and/or over-expression is an important component of the Program Project efforts to provide molecular descriptions of the roles played by the P450 enzymes in renal physiology or pathophysiology. Crucial to the success of these efforts is the timely and unrestricted access by the Program Project investigators to P450 mutant mice. The overall goals of the animal core (Core D) are to centralize the maintenance, breeding, and initial characterization of mice strains carrying P450 mutations induced by targeted gene disruption. It is expected that the proposed centralization will result in significant savings of time and money, lead to a more efficient utilization of common resources and expertise, and improve overall productivity and reproducibility. Specifically, Core D will receive from Project 2 breeder pairs containing mutated copies of genes coding for distinct P450 isoforms. Matting, backcross, and breeding techniques will be utilized for the generation of congenic (+/+), and (-/-) mice genotypes carrying either 129SvJ or C57BL/6J genetic backgrounds. Core D will also perform the initial morphological and functional evaluation of mice carrying mutated P450 genotypes. The centralization of these routine tasks in Core D will eliminate unnecessary and costly duplications and will provide projects 1-4 with the mutant animals needed for functional studies in a timely fashion. Cyp4a14 (-/-) and 4a10 (-/-) mice are already available in 129/SvJ background, and Cyp 4a14 (-/-) also in congenic C57BL/6J background. Cyp4a12 null mutants will available within the next 12-15 months. Cyp2c44 (-/-) mice will be developed within the next 2-3 years, and Cyp4a12 and 2c44 transgenics in years 3-4.