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Dual-color tumor-host imaging models

双色肿瘤宿主成像模型

基本信息

批准号：
7234290
负责人：
MENG YANG
金额：
$ 37.58万
依托单位：
ANTICANCER, INC.
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7234290
关键词：
Amino Acid Sequence Anesthesia procedures Animals Blood Vessels Breast Cells Code Colon Color Compatible Complex Darkness Detection Development Disease regression Drug Delivery Systems Elements Environment Erythrocytes Firefly Luciferases Fluorescence Genus Cola Green Fluorescent Proteins Hair Human Image Implant Injection of therapeutic agent Label Lentivirus Vector Life Light Luciferases Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Modeling Mus Neoplasm Metastasis Nude Mice Optics Organ Peptide Sequence Determination Pharmaceutical Preparations Phase Photons Process Proliferating Proteins Renilla Luciferases Reporter Reporter Genes Resolution Signal Transduction Simplexvirus Skin Solid Neoplasm Stromal Cells Stromal Neoplasm Surgical Flaps Techniques Testing Therapeutic Agents Thymidine Kinase Time Tissues Transplantation Tumor Angiogenesis Vascular blood supply Yang angiogenesis antiangiogenesis therapy anticancer research beta Actin cell type cellular imaging charge coupled device camera cost drug discovery fluorescence imaging high throughput screening host neoplasm interaction human cancer mouse model in vivo instrumentation interest luciferin mouse model mutant neoplastic cell nestin protein promoter red fluorescent protein response restraint therapeutic angiogenesis three dimensional structure tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): This Phase II application will further develop dual-color imageable tumor-host-interaction nude mouse models, developed in the Phase I application, to be used in Phase III to discover and evaluate new effective agents for stromal therapy, including angiogenesis. The host models are the ubiquitously-expressing green fluorescent protein (GFP)-nude mouse with GFP under control of the beta-actin promoter (BAD-GFP) (Yang, M., et al., Proc. Natl. Acad. Sci. USA 98, 2616-2621, 2001 and Yang, M., et al., Cancer Research, 64, 8651- 8656, 2004) and the nestin-driven-GFP (ND-GFP) nude mouse in which nascent blood vessels are labeled with GFP (Amoh, Y., et al., Cancer Res. 65, 5352-5357, 2005). All of the tissues of the BAD-GFP mice, with the exception of erythrocytes and hair, fluoresce green under blue excitation light. In ND-GFP mice, nascent blood vessels express GFP. Transplanted red fluorescent protein (RFP)-expressing tumors and GFP- expressing stromal cells can be clearly imaged simultaneously in the BAD-GFP models. Dual-color orthotopic models of human breast, colon and prostate cancer will be developed in both the BAD-GFP and ND-GFP models to image tumor-host interaction in both primary and resulting metastases. Dual-color imaging enables resolution of the tumor and the host tissues down to the single cell level. All tumor- interacting host stromal cells can be uniquely imaged in the BAD-GFP model including live mice. The stromal cells are targets for new stromal therapy. Nascent tumor angiogenesis can be uniquely imaged in the ND- GFP model. Nascent angiogenesis is a potentially critical target for antitumor and antimetastatic therapy and is uniquely visualized in human tumors in the live ND-GFP nude mouse. These color-coded nude mouse models of human cancer will be used to visualize new targets which should greatly enhance the discovery of stromal-targeting and anti-angiogenesis drugs. The specific aims include: (1) Development of dual-color tumor-host models with the BAD-GFP nude mouse with orthotopic RFP-expressing human tumors for discovery of stroma-targeted therapeutic agents. (2) Development of dual-color tumor-host models with the ND-GFP nude mouse with orthotopic RFP-expressing tumor models for discovery of specific agents which target nascent angiogenesis. These models have significant commercial potential for discovery and development of stroma-targeted and anti-angiogenesis drugs.

描述（由申请人提供）：本 II 期申请将进一步开发在 I 期申请中开发的双色可成像肿瘤-宿主相互作用裸鼠模型，用于 III 期发现和评估用于基质治疗（包括血管生成）的新有效药物。宿主模型是普遍表达的绿色荧光蛋白（GFP）裸鼠，其 GFP 受 β-肌动蛋白启动子（BAD-GFP）控制（Yang, M., et al., Proc. Natl. Acad. Sci. USA 98, 2616-2621, 2001 和 Yang, M., et al., Cancer Research, 64, 8651-8656, 2004）和巢蛋白驱动的 GFP (ND-GFP) 裸鼠，其中新生血管用 GFP 标记 (Amoh, Y., et al., Cancer Res. 65, 5352-5357, 2005)。 BAD-GFP 小鼠的所有组织（红细胞和毛发除外）在蓝色激发光下发出绿色荧光。在 ND-GFP 小鼠中，新生血管表达 GFP。移植的表达红色荧光蛋白 (RFP) 的肿瘤和表达 GFP 的基质细胞可以在 BAD-GFP 模型中同时清晰成像。将在 BAD-GFP 和 ND-GFP 模型中开发人类乳腺癌、结肠癌和前列腺癌的双色原位模型，以对原发性转移灶和由此产生的转移灶中的肿瘤-宿主相互作用进行成像。双色成像能够将肿瘤和宿主组织的分辨率降低到单细胞水平。所有与肿瘤相互作用的宿主基质细胞都可以在 BAD-GFP 模型中进行独特成像，包括活体小鼠。基质细胞是新基质疗法的靶标。新生肿瘤血管生成可以在 ND-GFP 模型中独特地成像。新生血管生成是抗肿瘤和抗转移治疗的潜在关键靶标，并且在活体 ND-GFP 裸鼠的人类肿瘤中独特地显现出来。这些颜色编码的人类癌症裸鼠模型将用于可视化新靶点，这将极大地促进基质靶向和抗血管生成药物的发现。具体目标包括：（1）利用表达原位RFP的人类肿瘤的BAD-GFP裸鼠开发双色肿瘤宿主模型，以发现基质靶向治疗药物。 (2)用ND-GFP裸鼠和原位表达RFP的肿瘤模型开发双色肿瘤宿主模型，以发现针对新生血管生成的特异性药物。这些模型对于发现和开发基质靶向药物和抗血管生成药物具有巨大的商业潜力。