Development of a Generic Pharmacodynamic Reporter Model for Assessing in vivo Activity and Selectivity of Targeted siRNA

短干扰RNA（siRNA）可以通过与mRNA（DNA和蛋白质的中间产物）结合并介导其降解来降低疾病相关基因的表达。然而，治疗性siRNA必须递送到身体的适当部位，这是一个重大挑战。如果器官不能直接进入，即皮肤、眼睛、肌肉，那么siRNA必须通过血流递送。目前还没有灵敏地确定到达活体动物中所需器官的siRNA的量和功效的方法。我们建议创造一种小鼠，它将在siRNA被递送的器官中表达光（由相机检测）。小鼠模型将通过将两段外源DNA引入小鼠的每个细胞中来创建，一段产生发光蛋白，另一段产生调节光表达的阻遏蛋白。当特异性识别阻遏物mRNA的siRNA进入细胞时，阻遏物蛋白的量将下降，并且将产生光。通过结合靶特异性和生物功能性，该模型将允许测试各种siRNA递送机制，从而改进设计和有效性。

Short interfering RNAs (siRNAs) can reduce the expression of disease-related genes by binding to and mediating the degradation of mRNA (the intermediate of DNA and protein) to which they are complementary. However therapeutic siRNA must be delivered to appropriate parts of the body which is a significant challenge. If the organs are not directly accessible i.e. skin, eyes, muscles, then siRNA must be delivered via the blood stream. Currently there are no methods to sensitively determine both the quantity and efficacy of siRNA reaching the desired organ in a living animal. We propose to create a mouse that will express light (detected by a camera) in organs where siRNA has been delivered. Mouse models will be created by introducing two pieces of foreign DNA into every cell in the mouse, one that makes light emitting protein and one that makes a repressor protein that regulates light expression. When siRNA that specifically recognises the repressor mRNA enters cells the amount of repressor protein will fall and light will be generated. By combining target specificity and biological functionality this model will permit testing of various siRNA delivery mechanisms leading to improved design and effectiveness.