Abstract
MR imaging of gene transcription is important as it should enable the non-invasive detection of mRNA alterations in disease. A range of MRI methods have been proposed for in vivo molecular imaging of cells based on the use of ultra-small super-paramagnetic iron oxide (USPIO) nanoparticles and related susceptibility weighted imaging methods. Although immunohistochemistry can robustly differentiate the expression of protein variants, there is currently no direct gene assay technique that is capable of differentiating established to differentiate the induction profiles of c-Fos mRNA in vivo. To visualize the differential FosB gene expression profile in vivo after burn trauma, we developed MR probes that link the T2* contrast agent [superparamagnetic iron oxide nanoparticles (SPION)] with an oligodeoxynucleotide (ODN) sequence complementary to FosB mRNA to visualize endogenous mRNA targets via in vivo hybridization. The presence of this SPION-ODN probe in cells results in localized signal reduction in T2*-weighted MR images, in which the rate of signal reduction (R2*) reflects the regional iron concentration at different stages of amphetamine (AMPH) exposure in living mouse tissue. Our aim was to produce a superior contrast agent that can be administered using systemic as opposed to local administration and which will target and accumulate at sites of burn injury. Specifically, we developed and evaluated a PEGylated lipid coated MR probe with ultra-small super-paramagnetic iron oxide nanoparticles (USPION, a T2 susceptibility agent) coated with cationic fusogenic lipids, used for cell transfection and gene delivery and covalently linked to a phosphorothioate modified oligodeoxynucleotide (sODN) complementary to c-Fos mRNA (SPION-cFos) and used the agent to image mice with leg burns. Our study demonstrated the feasibility of monitoring burn injury using MR imaging of c-Fos transcription in vivo, in a clinically relevant mouse model of burn injury for the first time.
Highlights
The well-known proto-oncogene, c-Fos, encodes a protein that plays key role in every kind of oxidative stress including burn trauma
Since c-Fos activation is implicated in numerous crucial intracellular functions such as cell cycle activity and apoptosis, regulation of signal transduction pathways, cellular trafficking, cell proliferation and differentiation, cell survival, and protein folding and proessing and its detection is important in establishing the pathology and path-physiology of burn and the regenerative processes [3]
The SNR in images acquired with 4 ms in the burn area is more intense compared to the contralateral area (Figure 3), a similar result was observed at TE = 14 ms (Figure 4)
Summary
The well-known proto-oncogene, c-Fos, encodes a protein that plays key role in every kind of oxidative stress including burn trauma. It has been reported that burns up-regulate the expression of c-Fos within six hours after injury and that this process is mediated through signals originating from the nucleus of monocytes and dermal fibroblasts. This up-regulation is mediated by the effect of protein growth factors that stimulate transcriptional activity and increase the delivery of Mrna to the cytoplasm [1,2,3]. Since c-Fos activation is implicated in numerous crucial intracellular functions such as cell cycle activity and apoptosis, regulation of signal transduction pathways, cellular trafficking, cell proliferation and differentiation, cell survival, and protein folding and proessing and its detection is important in establishing the pathology and path-physiology of burn and the regenerative processes [3].
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