Comprehensive MRI, MRS and Molecular Analyses: Pten-based Prostate Cancer Models

描述(由申请人提供)：这项建议利用了我的实验室开发的纵向非侵入性、高分辨率成像和光谱分析技术，结合了对基于Pten的小鼠前列腺癌(PCA)模型的大量尸检和体外分析，这些分析是专门为翻译研究而设计的。目的是了解前列腺癌发生和发展的生化和分子发病机制。我们的长期目标是将非侵入性成像与体外分析相结合，以确定前列腺癌的潜在生物标志物(例如，前列腺体积和生化变化)。这一建议将把前列腺的形态和代谢变化与潜在的细胞增殖分子标志物(如细胞周期蛋白D1、Ki-67)联系起来，以进一步了解前列腺癌的发生和发展到晚期癌症的机制。目的1.用核磁共振方法测定前列腺癌小鼠体内前列腺癌模型的前列腺体积。假设。在体内，纵向扩散加权成像和MR体积测量可以无创地识别和量化前列腺癌随着时间的变化而发生的形态变化。目的2.通过对小鼠前列腺癌模型进行在体磁共振波谱分析，确定在AIM 1中使用的小鼠前列腺上皮的生化变化。假设。在体内，MRS将有助于在生物相关的小鼠模型中识别PCA进展的生化标记物。目的3.确定Pten和ErbB-2在前列腺癌发生和发展过程中的信号转导途径。假设。Cyclin D1基因活性和Ki-67核染色的联合增加代表了前列腺癌进展的分子标记，并与前列腺大小和胆碱与柠檬酸比率的增加有关。这些目标集中在无创量化ErbB-2和Pten在体内对前列腺大小和新陈代谢的贡献，并使用补充的尸检分析来加深我们对启动和进展前列腺癌的分子机制的理解。这项建议将利用适当控制和充分的体内和体外研究(不能在人类身上进行的分析)来探索遗传学和年龄在前列腺癌中所起的作用。此外，使用人前列腺癌细胞系进行的补充体外实验允许在信号转导机制和靶基因表达方面对小鼠数据进行验证和扩展。我们对成像和癌症的综合方法直接适用于更好地理解临床PCa的机制。

DESCRIPTION (provided by applicant): This proposal makes use of longitudinal non-invasive, high-resolution imaging and spectroscopy techniques, which were developed in my laboratory, in combination with extensive post mortem and in vitro analyses of Pten-based mouse prostate cancer (PCa) models, specifically designed for use in translational. The goals are to understand the biochemical and molecular pathogenesis of prostate cancer initiation and progression. Our long-term goal is to combine non-invasive imaging with ex vivo analyses to define potential biomarkers of PCa (e.g., prostate volume and biochemical shifts). This proposal will correlate morphometric and metabolic changes in the prostate with potential molecular markers of cell proliferation (e.g., cyclin D1, Ki-67) to further our understanding of the mechanisms of PCa initiation and progression to advanced stage cancer. Aim 1. Determine the prostate growth volumetry in Pten-based in mouse models of PCa in vivo by MRI. Hypothesis. Longitudinal Diffusion Weighted Imaging and MR volumetry, in vivo, of PCa initiation and progression will allow for the non-invasive identification and quantification of morphometric changes in the prostate, over time. Aim 2. Identify biochemical changes in the prostate epithelium in mice used in Aim 1 through in vivo MR spectroscopy performed on mouse PCa models. Hypothesis. In vivo MRS will aid in identifying biochemical markers of PCa progression in biologically relevant mouse models. Aim 3. Determine the signaling pathways involved in the cross talk-between Pten and ErbB-2 during PCa initiation and progression. Hypothesis. Combined increases in cyclin D1 gene activity and Ki-67 nuclear staining represent molecular markers of PCa progression, and are associated with increased prostate size and choline:citrate ratios. These Aims are focused on non-invasively quantifying the contributions of ErbB-2 and Pten on prostate size and metabolism in vivo and to use complementary post mortem analyses to further our understanding of the molecular mechanisms involved in both initiating PCa and in its progression. This proposal will explore the role that both genetics and age play in PCa, using properly controlled and adequately powered in vivo and ex vivo studies (analyses which cannot be performed in humans). In addition, complementary in vitro experiments using human PCa cell lines allow for both validation and extension of the mouse data, with respect to mechanism of signal transduction and target gene expression. Our comprehensive approach to imaging and cancer has direct applicability to the better understanding the mechanisms of clinical PCa.