Rodriguez Susana, Wolfgang Michael J
Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Chem Biol. 2012 Mar 23;19(3):391-8. doi: 10.1016/j.chembiol.2011.12.022.
Loss- and gain-of-function transgenic models are powerful tools for understanding gene function in vivo but are limited in their ability to determine relative protein requirements. To determine cell-specific, temporal, or dose requirements of complex pathways, new methodology is needed. This is particularly important for deconstructing metabolic pathways that are highly interdependent and cross-regulated. We have combined mouse conditional transgenics and synthetic posttranslational protein stabilization to produce a broadly applicable strategy to regulate protein and pathway function in a cell-autonomous manner in vivo. Here, we show how a targeted chemical-genetic strategy can be used to alter fatty acid metabolism in a reombination and small-molecule-dependent manner in live behaving transgenic mice. This provides a practical, specific, and reversible means of manipulating metabolic pathways in adult mice to provide biological insight.
功能丧失和功能获得转基因模型是理解体内基因功能的强大工具，但在确定相对蛋白质需求方面能力有限。为了确定复杂途径的细胞特异性、时间或剂量需求，需要新的方法。这对于解构高度相互依赖和交叉调节的代谢途径尤为重要。我们将小鼠条件转基因与合成的翻译后蛋白质稳定化相结合，以产生一种广泛适用的策略，在体内以细胞自主的方式调节蛋白质和途径功能。在这里，我们展示了一种靶向化学遗传策略如何用于以重组和小分子依赖的方式在行为活跃的转基因小鼠中改变脂肪酸代谢。这为在成年小鼠中操纵代谢途径以提供生物学见解提供了一种实用、特异且可逆的方法。
