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

综合 MRI、MRS 和分子分析：基于 Pten 的前列腺癌模型

• 批准号: 7386397
• 负责人: CHRISTOPHER ALBANESE
• 金额: $ 29.17万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386397
• 关键词: Age; Animals; Area; Autopsy; Biochemical; Biochemical Markers; Biochemical Pathway; Biochemistry; Biological Markers; CCND1 gene; Cancer Model; Cell Proliferation; Choline Citrate; Clinical; Cyclin D1; Data; Development; Diagnostic Neoplasm Staging; Diffusion; Diffusion weighted imaging; Disease; Engineering; Epithelium; Event; Gene Expression; Gene Targeting; Genetic; Goals; Growth; Histopathology; Human; Image; In Vitro; Invasive; Laboratories; Lesion; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant neoplasm of prostate; Measures; Metabolic; Metabolism; Metastatic Prostate Cancer; Modeling; Molecular; Monitor; Mus; Nuclear; PC3 cell line; Pathogenesis; Play; Prostate; Prostatic Diseases; Resolution; Role; Sampling; Signal Pathway; Signal Transduction; Spectrum Analysis; Staining method; Stains; Structure of base of prostate; Techniques; Time; Tissues; Validation; Weight; animal data; base; cancer imaging; clinical Diagnosis; clinically significant; design; human subject; improved; in vivo; molecular pathology; mouse model; noninvasive diagnosis; research study; size; translational study; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：该提案利用了在我的实验室中开发的纵向非侵入性，高分辨率成像和光谱技术，并结合了验尸后的广泛分析和基于PTEN的小鼠前列腺癌（PCA）模型的大量分析，该模型是专门用于翻译的。目标是了解前列腺癌开始和进展的生化和分子发病机理。我们的长期目标是将非侵入性成像与离体分析相结合，以定义PCA的潜在生物标志物（例如前列腺体积和生化转移）。该建议将将前列腺中的形态计量学和代谢变化与细胞增殖的潜在分子标记（例如Cyclin d1，Ki-67）相关联，以进一步了解我们对PCA起始和进展机制与晚期阶段癌的理解。 AIM 1。确定MRI的PCA小鼠模型中基于PTEN的前列腺生长体积。假设。纵向扩散加权成像和MR体积，体内，PCA启动和进展将允许随着时间的流逝，前列腺中形态变化的非侵入性鉴定和定量。 AIM 2。在AIM 1中通过在小鼠PCA模型上进行的AIM 1中使用的小鼠中前列腺上皮的生化变化。假设。体内MRS将有助于鉴定生物学相关的小鼠模型中PCA进展的生化标志物。 AIM 3。确定PCA启动和进展过程中PTEN和ERBB-2之间涉及的信号传导途径。假设。 Cyclin D1基因活性和KI-67核染色的联合增加代表PCA进展的分子标记，并且与前列腺大小和胆碱的增加有关：柠檬酸含量。这些目标集中在非侵入性量化ERBB-2和PTEN对体内前列腺大小和代谢的贡献，并使用互补后验尸分析，以进一步了解我们对启动PCA及其进展及其进展的分子机制的理解。该提案将使用适当控制且充分供电的体内和离体研究（无法在人类进行的分析）探索遗传学和年龄在PCA中发挥的作用。此外，相对于信号转导和靶基因表达的机制，使用人PCA细胞系的互补体外实验允许验证和扩展小鼠数据。我们对成像和癌症的全面方法具有直接适用性，以更好地了解临床PCA的机制。