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

描述（由申请人提供）：本提案利用我的实验室开发的纵向无创、高分辨率成像和光谱技术，结合专门为翻译设计的基于pten的小鼠前列腺癌（PCa）模型的广泛尸检和体外分析。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离体分析相结合，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）。该建议将前列腺的形态计量学和代谢变化与细胞增殖的潜在分子标志物（例如，细胞周期蛋白D1， Ki-67）联系起来，以进一步了解前列腺癌起始和发展为晚期癌症的机制。目的1。以pten为基础的前列腺癌小鼠模型在体内的MRI测定前列腺生长体积。假设。纵向扩散加权成像和磁共振体积法，在体内，前列腺癌的发生和发展将允许无创识别和定量前列腺形态变化，随着时间的推移。目标2。通过对小鼠PCa模型进行体内磁共振光谱分析，确定Aim 1中使用的小鼠前列腺上皮的生化变化。假设。体内MRS将有助于识别生物相关小鼠模型中PCa进展的生化标志物。目标3。确定前列腺癌起始和进展过程中Pten和ErbB-2之间的信号通路。假设。cyclin D1基因活性和Ki-67核染色的联合升高代表了前列腺癌进展的分子标记，并且与前列腺大小和胆碱：柠檬酸盐比值的增加有关。这些目标集中在无创量化ErbB-2和Pten对体内前列腺大小和代谢的贡献，并使用互补的死后分析来进一步了解前列腺癌启动及其进展的分子机制。本提案将探索遗传和年龄在PCa中的作用，使用适当控制和充分支持的体内和离体研究（无法在人类中进行的分析）。此外，利用人PCa细胞系进行的互补体外实验允许在信号转导和靶基因表达机制方面验证和扩展小鼠数据。我们对影像学和癌症的综合研究方法直接适用于更好地理解临床前列腺癌的机制。

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.