PROSTATE DEVELOPMENT USING CRE RECOMBINASE

一种新的转基因小鼠模型(称为PB-cre)已经被衍生出来，在该模型中，cre重组酶在前列腺特异性前盆启动子的控制下在雄性前列腺癌中特异表达，用于研究前列腺癌的发育。在这个R2L应用中，我们首先建议描述该转基因的表达模式，并确定随着时间的推移条件基因重组的开始和程度。然后，我们建议选择性地突变正常小鼠和遗传性前列腺上皮异型增生小鼠的前列腺上皮中的维甲酸受体RXRα：基因。具体目的1：明确pB-cre转基因驱动的重组模式。通过与特征明确的条件报告基因ROSA26R(R26R)杂交，可以全面描述由该转基因驱动的重组的时机和程度。特定目的2：选择性突变前列腺上皮中的RXRα基因。大量先前和新的证据表明，维甲酸和维甲酸受体，特别是RXRα：，在前列腺上皮的形成和维持以及前列腺癌的进展中起着重要作用。我们将把表达CRC的转基因与条件等位基因RXRα：杂交，并评估前列腺上皮形态改变的性质和程度。我们还将RXRα：的条件突变引入Nkx3。L基因敲除小鼠模型评估RXRα：在多大程度上调控前列腺异常增生和癌症的发生和发展。

A new transgenic mouse model (called PB-cre), in which cre recombinase is expressed specifically in the male prostate under the control of the prostate-specific probasin promoter, has been derived for the study of prostate development and cancer. In this R2l application, we first propose to characterize the expression pattern of this transgene and to define the onset and extent of recombination over time of conditional genes. We then propose to selectively mutate the retinoid receptor RXR alpha: gene in prostatic epithelium in normal mice and in mice genetically disposed to prostatic epithelial dysplasia. Specific Aim 1: To define the pattern of recombination driven by the PB- cre transgene. A comprehensive description of the timing and extent of recombination as driven by this transgene will be obtained by crossing to the well-characterized conditional reporter gene ROSA26R (R26R). Specific Aim 2: To selectively mutate the RXR alpha: gene in prostate epithelium. Abundant prior and new evidence presented in this proposal implicate a role for retinoids and retinoid receptors, particularly RXR alpha:, in the derivation and maintenance of prostatic epithelium and in the progression of prostate cancer. We will cross the crc-expressing transgene with a conditional allele of RXR alpha:, and evaluate the nature and extent of morphological alterations in the prostatic epithelium. We will also cross the conditional mutation of RXR alpha: into the Nkx3. l knockout mouse model to evaluate the extent to which RXR alpha: modulates the initiation and progression of prostate dysplasia and cancer.