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Human Copper Transporter 1 as Reporter Gene for Imaging

人类铜转运蛋白 1 作为成像报告基因

基本信息

批准号：
7752691
负责人：
FANGYU PENG
金额：
$ 14.69万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7752691
关键词：
Affinity Animal Model Bladder Brain Cells Cervix carcinoma Cisplatin Clinical Trials Copper Data Dependovirus Development Dopamine Receptor Drug or chemical Tissue Distribution Ensure Experimental Animal Model Gene Delivery Genes Half-Life Head and Neck Cancer Hela Cells Hepatic Hepatic Tissue Herpesviridae Hour Human Human body Image Imaging Techniques Invasive Liver Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Mediating Monitor Mus Neuroblastoma Oncogene Proteins Oncogenes Organ Pattern Phosphotransferases Pilot Projects Positron-Emission Tomography Prostate Purpose Radioactive Reaction Reporter Reporter Genes Reporting Research Personnel Safety Salivary Glands Signal Transduction Site Tissues Tracer Tumor Tissue Viral Xenograft procedure adeno-associated viral vector base chemotherapeutic agent copper transporter 1 gene therapy in vivo innovation manufacturing facility molecular imaging novel programs promoter research study size sodium-iodide symporter therapeutic gene transgene expression tumor tumor xenograft uptake vector

项目摘要

DESCRIPTION (provided by applicant): It is essential to monitor transgene expression for efficacy and safety of human gene therapy. Use of a reporter gene to monitor gene delivery and expression in targeted tissue represents an innovative molecular imaging technique. After simultaneous delivery of a reporter gene with a therapeutic gene, imaging signals from a reporter gene indirectly reflect the distribution and expression of a therapeutic gene in vivo. Because there are some limitations associated with the reporter genes currently available, it is necessary to search for new reporter genes which may be used when use of other reporter genes is limited. Human copper transporter 1 (hCtrl) gene encodes a high affinity copper transporter. Endogenous hCtrl is highly expressed in liver, with much lower expression in extra-hepatic tissues. Here, we hypothesize that hCtrl may be used as a reporter gene for imaging gene delivery in vivo by PET. We will perform exploratory experiments with two specific aims. AIM 1: To determine whether over-expression of hCtrl in tumor tissue can be imaged non-invasively and quantitatively by Cu-64 PET, using human cervical carcinoma xenograft in mice as an experimental animal model. AIM 2: To evaluate feasibility using hCtrl as a reporter gene for imaging transcriptional targeting of hCtrl expression to tumor over-expressing N-MYC oncoprotein by Cu-64 PET, using human neuroblastoma xenograft in mice as an animal model. This new reporter gene may have unique desirable features in comparison to other reporter genes: 1) hCtrl will not stimulate immunological reaction in humans and is expected to be very useful for longitudinal monitoring of transgene expression non-invasively and quantitatively; 2) the hCtrl reporter gene is expected to be especially useful for imaging targeted gene delivery in prostate cancer gene therapy because there is little background activity in the urinary bladder; 3) hCtrl holds potential as a therapeutic gene based on its capability to medicate cellular uptake of cisplatin. The data from this pilot study will help us to determine whether it is feasible to use hCtrl as a reporter gene for imaging. Successful development of this new hCtrl reporter gene is expected to contribute to advance of human gene therapy significantly by providing a versatile reporter gene for longitudinal monitor of transgene expression in vivo non-invasively and qunatitatively by PET imaging.

描述(由申请人提供)：监测转基因表达对于人类基因治疗的有效性和安全性是必不可少的。使用报告基因来监测基因在靶组织中的传递和表达，代表了一种创新的分子成像技术。报告基因与治疗基因同时传递后，来自报告基因的成像信号间接反映了治疗基因在体内的分布和表达。由于目前已有的报告基因存在一定的局限性，因此有必要寻找新的报告基因，以便在其他报告基因使用受限的情况下加以利用。人铜转运蛋白1(HCtrl)基因编码一种高亲和力的铜转运蛋白。内源性hCtrl在肝脏中高表达，在肝外组织中低表达。在此，我们假设hCtrl可能作为PET体内基因传递成像的报告基因。我们将进行探索性实验，具体目标有两个。目的：以人宫颈癌裸鼠移植瘤为实验动物模型，探讨铜-正电子发射计算机断层扫描技术能否无创性定量显示hCtrl在肿瘤组织中的过度表达。目的：以人神经母细胞瘤小鼠移植瘤为动物模型，探讨以hCtrl为报告基因，通过铜-正电子发射计算机断层扫描(PET)技术，对高表达N-myc癌蛋白的肿瘤进行hCtrl基因转录靶向成像的可行性。与其他报告基因相比，这个新的报告基因可能具有独特的可取功能：1)hCtrl不会刺激人体的免疫反应，有望非常有用地无创和定量地纵向监测转基因表达；2)hCtrl报告基因有望在前列腺癌基因治疗的靶向基因治疗成像中特别有用，因为它在膀胱中几乎没有背景活性；3)hCtrl具有潜在的治疗基因的能力，因为它能够药物治疗细胞对顺铂的摄取。这项先导性研究的数据将有助于我们确定使用hCtrl作为报告基因进行成像是否可行。这种新的hCtrl报告基因的成功开发有望为人类基因治疗的发展做出重大贡献，为利用PET成像无创、定量地监测转基因在体内的表达提供一个通用的报告基因。