Na+/I- symporter (NIS) is an intrinsic membrane glycoprotein that mediates active iodide uptake into thyroid follicular cells. We and others have shown that NIS gene transfer can induce iodide uptake into a variety of cells and that xenografts expressing exogenous NIS could be imaged in vivo. These data suggest that NIS expression and function could be measured quantitatively in vivo based on NIS' ability to uptake radioiodide. Thus, NIS may serve as an imaging reporter gene (""""""""lmagene"""""""") to optimize vector delivery, to monitor therapeutic gene expression, and to map the tissue/organ sites of repopulated progenitor cells in vivo. The proposed project aims to address the two parameters that are vital to the usefulness of NIS as an Imagene: acceptable signal-to-noise ratio and conditions in which a linear relationship exists between gene expression and measured signal levels. We hypothesize that these two parameters will vary, based upon target cells and in vivo host environment. We will determine the relative importance of NIS expression levels and the number of NIS expressing cells required for in vivo imaging in tissues of different signal to noise ratios.
Four specific aims are identified:
Aim 1. Determine the range of NIS expression levels that correlate with radioiodide accumulation in cultured cells;
Aim 2. Determine the NIS expression levels and the number of NIS expressing cells required for in vivo imaging in subcutaneous xenografts;
Aim 3. Investigate the different NIS expression levels required for in vivo imaging in internal organs with different signal to noise ratios;
and Aim 4. Evaluate the feasibility of NIS as an imaging reporter gene to monitor therapeutic gene expression in a preclinical animal model. The success of the proposed studies will allow us to proceed to human clinical trials using NIS as an Imagene to ensure targeted and effective gene transfer and to track repopulated progenitor cells in vivo.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Special Emphasis Panel (ZRG1-F05 (50))
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Zhang, Yantian
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Ohio State University
Schools of Medicine
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Zhang, Zhaoxia; Beyer, Sasha; Jhiang, Sissy M (2013) MEK inhibition leads to lysosome-mediated Na+/I- symporter protein degradation in human breast cancer cells. Endocr Relat Cancer 20:241-50
Brandt, Michael P; Kloos, Richard T; Shen, Daniel H et al. (2012) Micro-single-photon emission computed tomography image acquisition and quantification of sodium-iodide symporter-mediated radionuclide accumulation in mouse thyroid and salivary glands. Thyroid 22:617-24
Liu, Yu-Yu; Brandt, Michael P; Shen, Daniel H et al. (2011) Single photon emission computed tomography imaging for temporal dynamics of thyroidal and salivary radionuclide accumulation in 17-allyamino-17-demothoxygeldanamycin-treated thyroid cancer mouse model. Endocr Relat Cancer 18:27-37
Knostman, Katherine A B; Venkateswaran, Anjli; Zimmerman, Bevin et al. (2007) Creation and characterization of a doxycycline-inducible mouse model of thyroid-targeted RET/PTC1 oncogene and luciferase reporter gene coexpression. Thyroid 17:1181-8
Vadysirisack, Douangsone D; Chen, Eric S-W; Zhang, Zhaoxia et al. (2007) Identification of in vivo phosphorylation sites and their functional significance in the sodium iodide symporter. J Biol Chem 282:36820-8
Vadysirisack, Douangsone D; Venkateswaran, Anjli; Zhang, Zhaoxia et al. (2007) MEK signaling modulates sodium iodide symporter at multiple levels and in a paradoxical manner. Endocr Relat Cancer 14:421-32
Knostman, Katherine A B; McCubrey, James A; Morrison, Carl D et al. (2007) PI3K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer. BMC Cancer 7:137
Vadysirisack, Douangsone D; Shen, Daniel H; Jhiang, Sissy M (2006) Correlation of Na+/I- symporter expression and activity: implications of Na+/I- symporter as an imaging reporter gene. J Nucl Med 47:182-90
Morgenstern, Kenneth E; Vadysirisack, Douangsone D; Zhang, Zhaoxia et al. (2005) Expression of sodium iodide symporter in the lacrimal drainage system: implication for the mechanism underlying nasolacrimal duct obstruction in I(131)-treated patients. Ophthal Plast Reconstr Surg 21:337-44
Zhang, Zhaoxia; Liu, Yu-Yu; Jhiang, Sissy M (2005) Cell surface targeting accounts for the difference in iodide uptake activity between human Na+/I- symporter and rat Na+/I- symporter. J Clin Endocrinol Metab 90:6131-40