siRNA for Drug Target Validation in Mammalian Cells

描述（由申请人提供）：医学和基因组学的巨大进步已经产生了大量新的候选药物靶标。然而，越来越明显的是，药物发现过程中的主要瓶颈并不总是药物设计本身，而是确定哪些候选靶标对特定疾病状态的贡献最大。 最近，一种革命性的新方法，称为RNA干扰（RNAi）已被证明是非常有效的抑制特定的靶基因在哺乳动物细胞中的表达在体外。SBIR Fast Track资助申请中提出的研究的总体目标是开发RNAi在体外和体内哺乳动物细胞中用于药物靶点验证的用途。在第一阶段的研究中，我们将开发试剂的siRNA的交付和探索的效用siRNA抑制报告基因表达的哺乳动物细胞在体外。在II期研究中，我们将RNAi技术应用于胰岛素信号转导途径的组成部分，作为原理验证测试。我们还将探索使用RNAi技术来抑制小动物中的基因表达，以在体内验证药物靶点。

DESCRIPTION (provided by applicant): The tremendous progress made in the medical sciences and genomics has given rise to a plethora of new candidate drug targets. However, it is becoming increasingly apparent that a major bottleneck in the drug discovery process is not always drug design per se, but rather identification of which of the candidate targets most contributes to the particular diseased state. Recently, a revolutionary new method termed RNA interference (RNAi) has been shown to be highly effective at inhibiting the expression of specific target genes in mammalian cells in vitro. The overall objective of the studies proposed in this SBIR Fast Track grant application is to develop the use of RNAi for the purposes of drug target validation in mammalian cells in vitro and in vivo. In Phase I studies, we will develop reagents for delivery of siRNA and explore the utility of siRNA for inhibiting reporter gene expression in mammalian cells in vitro. In Phase II studies, we will apply RNAi technology to components of the insulin signal transduction pathway as a proof-of-principle test. We will also explore the use of RNAi technology to inhibit expression of genes in small animals in order to validate drug targets in vivo.