Mouse Cancer Models for Integrated Tissue/Serum Proteomics and Molecular Imaging

用于整合组织/血清蛋白质组学和分子成像的小鼠癌症模型

• 批准号: 7067900
• 负责人: SANJIV S GAMBHIR
• 金额: $ 41.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067900
• 关键词: antineoplastics; bioimaging /biomedical imaging; biomarker; cell surface receptors; clinical research; cooperative study; disease /disorder model; electron crystallography; immunomagnetic separation; laboratory mouse; microarray technology; microprocessor /microchip; molecular /cellular imaging; nanotechnology; neoplasm /cancer diagnosis; neoplasm /cancer therapy; neoplastic process; prognosis; protein binding; protein quantitation /detection; proteomics; quantum chemistry; technology /technique development; xenotransplantation

Nanotechnology has the potential to significantly impact the development of small animal models of cancer including models to test new antineoplastic therapies. In this project we will develop mouse tumor xenoqraft models that will allow us to test if we can combine both tissue/serum nanosensor based proteomic analysis and molecular imaging with targeted fluorescent quantum dots to predict and monitor treatment response with specific therapies. These models are important to the overall vision of this CCNE-TR for which would like to eventually utilize ex vivo nanosensors and in vivo molecular imaging in cancer patients for improving how we predict and monitor response to therapies. In Aim 1 we will optimize small animal optical imaging instrumentation for imaging quantum dots and also work with General Electric Global Research to develop and test a new frequency domain optical imaging instrument. In Aim 2 we will utilize biologically targeted quantum dots developed in Projects 5 and 6 to image tumors in living mice. We will proceed systematically from targeting one known tumor cell surface antigen (CD20 in our lymphoma xenograft model) to targeting several known tumor cell surface antigens (her2/her3/PSCA in our prostate cancer model), before expanding our target range to neovascularization (avp3 Integrin) and extracellular matrix targets (Matrix metalloproteinase 2, MMP2). In Aim 3 we will develop mouse models of lymphoma for testing antineoplastic therapies in order to study changes in proteins at the cell membrane, in the secretome, and in serum. Cell surface and serum proteome will be analyzed by Solid Phase Extraction of Glycoproteins (SPEC) and Liquid Chromatography Mass Spectrometry (SPEG/MS), whereas secretome will be assessed by biotin capture and subsequent cellular functional profiling array for changes that are predictive of response to therapy. We will test two lymphoma therapy models, one xenograft model for human lymphoma mimicking response vs. resistance to Rituxan therapy, and a mouse pre-clinical model of response vs. resistance to targeted inactivation of the MYC oncogene. In Aim 4 we will test a mouse cancer model using the results from the previous three aims in order to determine the utility of integrating ex vivo and in vivo nanotechnologies to determine protein changes in the tissue/serum and to image molecular changes pre and post-therapy. The significance of this work is that it should help set the foundation for using ex vivo nanosensors in clinical trials, to allow development of novel molecular imaging probes for clinical trials, and to improve drug testing in small animal cancer models. This should lead to marked improvement in predicting and monitoring response to therapy in cancer patients.

纳米技术有可能显着影响癌症小动物模型的发展 包括测试新的抗塑性疗法的模型。在这个项目中，我们将开发小鼠肿瘤Xenoqraft 将使我们能够测试是否可以结合组织/血清纳米传感器的蛋白质组学分析的模型 和具有靶向荧光量子点的分子成像，以预测和监测治疗响应 有特定的疗法。这些模型对于此CCNE-TR的整体视野很重要 喜欢最终利用癌症患者的体内纳米传感器和体内分子成像来改善 我们如何预测和监测对疗法的反应。在AIM 1中，我们将优化小动物光学成像 用于成像量子点的仪器，并与通用全球研究一起开发 并测试新的频域光学成像仪器。在AIM 2中，我们将利用以生物学为目标的 在项目5和6中开发的量子点为活小鼠的肿瘤成像。我们将系统地进行 从靶向一种已知的肿瘤细胞表面抗原（我们的淋巴瘤模型中的CD20）到靶向 在扩展之前 我们对新血管化的目标范围（AVP3整合素）和细胞外基质靶标（矩阵 金属蛋白酶2，MMP2）。在AIM 3中，我们将开发淋巴瘤的小鼠模型，以测试抗肿瘤 疗法是为了研究细胞膜，分泌组和血清的蛋白质变化。细胞 表面和血清蛋白质组将通过糖蛋白（SPEC）和液体的固相提取进行分析 色谱质谱法（SPEG/MS），而分泌组将通过生物素捕获评估 以及随后的细胞功能分析阵列，以预测对治疗反应的变化。我们 将测试两种淋巴瘤疗法模型，一种模仿人类淋巴瘤的异种移植模型VS。 抗rituxan疗法的抗性，以及小鼠的临时响应前临床模型与对靶向的抗性 MYC癌基因失活。在AIM 4中，我们将使用来自 以前的三个目标是为了确定将离体和体内纳米技术集成到的实用性 确定组织/血清中的蛋白质变化，并在治疗前和疗法后成像分子变化。这 这项工作的重要性是，它应该有助于在临床中使用离体纳米传感器奠定基础 试验，允许开发新的分子成像探针进行临床试验，并改善药物测试 在小动物癌模型中。这应该导致预测和监视的明显改善 对癌症患者治疗的反应。