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

描述（由申请人提供）：本提案使用了在我的实验室开发的纵向非侵入性、高分辨率成像和光谱技术，并结合了对基于Pten的小鼠前列腺癌（PCa）模型的广泛尸检和体外分析，该模型专门设计用于转化。目的是了解前列腺癌发生和发展的生物化学和分子发病机制。我们的长期目标是将联合收割机非侵入性成像与离体分析相结合，以确定PCa的潜在生物标志物（例如，前列腺体积和生化变化）。该提议将前列腺中的形态测量和代谢变化与细胞增殖的潜在分子标志物（例如，cyclin D1，Ki-67）的表达，以进一步了解PCa发生和进展为晚期癌症的机制。目标1。通过MRI测定Pten在PCa小鼠体内模型中前列腺生长体积。假说. PCa启动和进展的体内纵向扩散加权成像和MR体积测定将允许无创识别和定量前列腺随时间的形态学变化。目标二。通过在小鼠PCa模型上进行的体内MR波谱分析，确定目标1中使用的小鼠前列腺上皮的生化变化。假说.体内MRS将有助于在生物学相关的小鼠模型中鉴定PCa进展的生化标志物。目标3：确定PCa启动和进展期间Pten和ErbB-2之间串扰所涉及的信号通路。假说.细胞周期蛋白D1基因活性和Ki-67核染色的联合增加代表了PCa进展的分子标志物，并与前列腺大小和胆碱：柠檬酸盐比率增加相关。这些目标的重点是非侵入性定量ErbB-2和Pten对前列腺大小和体内代谢的贡献，并使用互补的尸检分析，以进一步了解参与启动PCa及其进展的分子机制。该提案将探索遗传学和年龄在PCa中发挥的作用，使用适当控制和充分的体内和离体研究（无法在人体中进行的分析）。此外，使用人前列腺癌细胞系的补充体外实验允许验证和扩展小鼠数据，关于信号转导和靶基因表达的机制。我们对影像学和癌症的综合方法对更好地理解临床PCa的机制具有直接适用性。

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.