Divalent metal transporter, DMT1: A novel MRI reporter protein

Bartelle, Benjamin B.; Szulc, Kamila U.; Suero-Abreu, Giselle Alexandra; Rodriguez, Joe J.; Turnbull, Daniel H.

doi:10.1002/mrm.24948

Cited by 3 publications

(3 citation statements)

References 40 publications

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“…Of interest, we previously showed that by engineering glioma cells to overexpress the Divalent Metal Transporter, DMT1, we were able to convert negative to positive contrast using the same MEMRI protocol. 53 This suggests that Mn uptake and storage is likely to be highly dependent on the set of F I G U R E 1 0 Results from the PLX5622 preclinical trial show response to therapy is heterogeneous and tumor model-dependent. (A) From the aggregate longitudinal tumor volume data from the aSmo-1 model, it was apparent that growth of CTL-treated tumors (blue) did not differ significantly from the growth of PLX-treated tumors (red) after treatment start at W7.…”

Section: F I G U R E 7 Tumor Centroid and Heatmap Analysis Illustratesmentioning

confidence: 99%

MEMRI‐based imaging pipeline for guiding preclinical studies in mouse models of sporadic medulloblastoma

Rallapalli

Tan

Volkova

et al. 2019

Magnetic Resonance in Med

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Purpose Genetically engineered mouse models of sporadic cancers are critical for studying tumor biology and for preclinical testing of therapeutics. We present an MRI‐based pipeline designed to produce high resolution, quantitative information about tumor progression and response to novel therapies in mouse models of medulloblastoma (MB). Methods Sporadic MB was modeled in mice by inducing expression of an activated form of the Smoothened gene (aSmo) in a small number of cerebellar granule cell precursors. aSmo mice were imaged and analyzed at defined time‐points using a 3D manganese‐enhanced MRI‐based pipeline optimized for high‐throughput. Results A semi‐automated segmentation protocol was established that estimates tumor volume in a time‐frame compatible with a high‐throughput pipeline. Both an empirical, volume‐based classifier and a linear discriminant analysis‐based classifier were tested to distinguish progressing from nonprogressing lesions at early stages of tumorigenesis. Tumor centroids measured at early stages revealed that there is a very specific location of the probable origin of the aSmo MB tumors. The efficacy of the manganese‐enhanced MRI pipeline was demonstrated with a small‐scale experimental drug trial designed to reduce the number of tumor associated macrophages and microglia. Conclusion Our results revealed a high level of heterogeneity between tumors within and between aSmo MB models, indicating that meaningful studies of sporadic tumor progression and response to therapy could not be conducted without an imaging‐based pipeline approach.

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Section: F I G U R E 7 Tumor Centroid and Heatmap Analysis Illustratesmentioning

confidence: 99%

MEMRI‐based imaging pipeline for guiding preclinical studies in mouse models of sporadic medulloblastoma

Rallapalli

Tan

Volkova

et al. 2019

Magnetic Resonance in Med

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“…To address the potentially restrictive role of iron import machinery, one study proposed co-expressing Ft with the transferrin receptor, a natural participant in cellular iron transport [78]. A conceptually related strategy involves using overexpression of paramagnetic metal ion transporters themselves to induce MRI contrast; contrast changes in rodents have been reported using the magnetotactic bacterial protein MagA [79] and the mammalian divalent cation transporter DMT1 [80], but it is not clear which specific metalloproteins might be involved in binding the metal ions once they have entered cells.…”

Section: Natural Metalloproteins In Mrimentioning

confidence: 99%

Metalloprotein‐based MRI probes

Matsumoto

Jasanoff

2013

FEBS Letters

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Metalloproteins have long been recognized as key determinants of endogenous contrast in magnetic resonance imaging (MRI) of biological subjects. More recently, both natural and engineered metalloproteins have been harnessed as biotechnological tools to probe gene expression, enzyme activity, and analyte concentrations by MRI. Metalloprotein MRI probes are paramagnetic and function by analogous mechanisms to conventional gadolinium or iron oxide-based MRI contrast agents. Compared with synthetic agents, metalloproteins typically offer worse sensitivity, but the possibilities of using protein engineering and targeted gene expression approaches in conjunction with metalloprotein contrast agents are powerful and sometimes definitive strengths. This review summarizes theoretical and practical aspects of metalloprotein-based contrast agents, and discusses progress in the exploitation of these proteins for molecular imaging applications.

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“…Previous efforts to develop such reporters have focused primarily on two classes of proteins. In one class, metalloproteins and metal ion transporters are overexpressed to enrich the paramagnetic content of cells, thereby enhancing nuclear relaxation rates and producing contrast in T1 or T2-weighted MRI 9,[12][13][14][15][16][17][18][19][27][28][29] . In the second strategy, proteins with large numbers of basic amino acids are used to generate contrast through chemical exchange saturation transfer (CEST) between protein-bound and aqueous protons 6,8,21,22,25,30 .…”

Section: Introductionmentioning

confidence: 99%

A Genetically Encoded Reporter for Diffusion Weighted Magnetic Resonance Imaging

Mukherjee

Davis

et al. 2016

Preprint

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The ability to monitor gene expression in intact, optically opaque animals is important for a multitude of applications including longitudinal imaging of transgene expression and long term tracking of cell based therapeutics. Magnetic resonance imaging (MRI) could enable such monitoring with high spatial and temporal resolution. However, existing MRI reporter genes, based primarily on metal-binding proteins or chemical exchange saturation transfer probes, are limited by their reliance on metal ions or relatively low sensitivity. In this work, we introduce a new class of genetically encoded reporters for MRI that work by altering water diffusivity. We show that overexpression of the human water channel aquaporin 1 (AQP1) produces robust contrast in diffusion weighted MRI by increasing effective water diffusivity in tissues by over 100% without affecting cell viability or morphology. Low levels of AQP1 expression (~1 μM), or mixed populations comprising as few as 10% AQP1-expressing cells, produce sufficient contrast to be observed by MRI. We demonstrate the utility of AQP1 in vivo by imaging gene expression in intracranial tumor xenografts. Overall, our results establish AQP1 as a new, metal-free, nontoxic and sensitive genetically encoded reporter for diffusion weighted MRI.

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Divalent metal transporter, DMT1: A novel MRI reporter protein

Cited by 3 publications

References 40 publications

MEMRI‐based imaging pipeline for guiding preclinical studies in mouse models of sporadic medulloblastoma

MEMRI‐based imaging pipeline for guiding preclinical studies in mouse models of sporadic medulloblastoma

Metalloprotein‐based MRI probes

A Genetically Encoded Reporter for Diffusion Weighted Magnetic Resonance Imaging

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