HR-MAS-pathologic correlation of prostate tissue markers

描述（由申请人提供）：这项拟议的研究职业奖建立在首席研究员作为NIH研究员的工作基础上，涉及使用磁共振波谱来改进前列腺癌的表征。前列腺癌是一种折磨着五分之一美国男性的疾病；然而，很难预测哪些癌症会扩散（转移）并威胁到生命，而哪些癌症会保持惰性。磁共振成像和光谱成像（MRI/3D-MRSI）已经证明能够：改善前列腺癌在腺体内的定位；评估疾病的囊外扩散；并提供治疗效果的衡量标准。作为NIH博士后，首席研究员利用MRI/3D-MRSI研究激素消融治疗前列腺癌患者的代谢影响，并开发了高分辨率魔角旋转（HR-MAS）技术用于离体前列腺癌组织分析。本研究的目的是通过改善与疾病相关的潜在生化、形态学和遗传变化的相关性，更好地表征MRSI在体内和HR-MAS在体外观察到的代谢变化。为了实现这些目标，我们将使用多维HR-MAS技术来识别可以在体内利用的新的代谢标志物，并基于扩散的实验来更多地了解前列腺代谢物的细胞内和细胞外分布。此外，我们将把我们的HR-MAS发现与改进的病理分析相结合，以更准确地将特定代谢谱与前列腺组织类型相关联。将进行免疫组织化学分析，将代谢谱与细胞增殖和凋亡的其他标志物联系起来。我们还将通过原子吸收分光光度法测定前列腺组织中的锌水平和实时逆转录酶聚合酶链式反应分析锌转运蛋白基因表达来研究锌变化对柠檬酸盐代谢的影响。这些方法将用于更多地了解激素依赖和独立条件下柠檬酸盐代谢的变化，使用转基因小鼠前列腺腺癌（TRAMP）模型。这项研究的具体目标的完成将为首席研究员提供开发他自己独立的癌症成像研究项目所需的额外工具。UCSF是一个领先的前列腺癌研究中心，拥有nci指定的综合癌症中心和前列腺孢子项目。这种优秀的研究环境与导师丰富的研究经验相结合，将极大地促进本提案中设定的目标的完成。

DESCRIPTION (provided by applicant): This proposed research career award builds on the principal investigator's work as an NIH fellow involving the use of magnetic resonance spectroscopy for the improved characterization of prostate cancer. Prostate cancer is a disease that afflicts one in five American men; however, it is difficult to predict those cancers that will spread (metastasize) and become life threatening from those that will remain indolent. Combined Magnetic Resonance Imaging and Spectroscopic Imaging (MRI/3D-MRSI) has demonstrated the ability to: improve the localization of prostate cancer within the gland; assess the extracapsular spread of the disease; and provide a measure of therapeutic response. As an NIH postdoctoral fellow, the principal investigator used MRI/3D-MRSI to study the metabolic effects of hormone ablation therapy in prostate cancer patients, and developed high resolution magic angle spinning (HR-MAS) techniques for the analysis of ex vivo prostate cancer tissues. The goal of this study is to better characterize the metabolic changes observed in vivo by MRSI and ex vivo by HR-MAS by improving their correlation with the underlying biochemical, morphologic, and genetic changes associated with the disease. To achieve these goals, we will use multidimensional HR-MAS techniques to identify new metabolic markers which can be exploited in vivo, and diffusion based experiments to learn more about the intracellular vs. extracellular distribution of prostate metabolites. Further, we will combine our HR-MAS findings with improved pathologic analysis to more accurately correlate specific metabolic profiles with prostate tissue type. Immunohistochemical assays will be performed to correlate metabolic profiles with other markers for cellular proliferation and apoptosis. We will also investigate the impact of zinc changes on citrate metabolism by assaying zinc levels in prostate tissues by atomic absorption spectrophotometry and zinc transporter gene expression using real-time reverse-transcriptase polymerase chain reaction analysis. These methods will then be used to learn more about changes in citrate metabolism under hormone dependent and independent conditions, using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The completion of the specific aims of this study will provide the principal investigator with the additional tools needed to develop his own independent cancer imaging research program. UCSF is a leading prostate cancer research center, with an NCI-designated comprehensive cancer center and prostate SPORE program. This excellent research environment combined with the extensive research experience of the mentor will greatly facilitate the completion of the goals set out in this proposal.