Paul D. Hockings

Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean

Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.

Magnetic resonance imaging of experimental mouse colitis and association with inflammatory activity

Background: Ulcerative colitis and Crohns disease are the major chronic inflammatory bowel diseases affecting the gastrointestinal tract in humans. Imaging techniques such as endoscopy and computed tomography are used to monitor disease activity. Magnetic resonance imaging (MRI) is emerging as a diagnostic modality, and studies have shown that MRI can be used in the diagnostic procedure of patients with inflammatory bowel disease. The aim of the present study was to investigate the role of MRI in quantitatively reflecting inflammation in an experimental mouse colitis model. Methods: Colonic inflammation was induced by exposing mice to dextran sulfate sodium. MRI was used to assess colon wall thickness, T2‐weighted (T2w) signal, and contrast‐enhanced T1‐weighted (T1w) signal in inflamed and healthy animals in vivo. Haptoglobin and interleukin‐1&bgr; served as systemic and local inflammatory markers, and macroscopic ex vivo scoring of the colon was performed to assess colonic inflammation. Results: Dextran sulfate sodium‐exposed animals displayed increased levels of inflammatory markers and higher inflammatory score compared with healthy animals. Colon wall thickness and contrast‐enhanced T1w signal were significantly increased in dextran sulfate sodium‐exposed compared with healthy animals. In addition, the T2w signal was positively correlated with haptoglobin levels and colon wall thickness in the inflamed animals. Conclusions: Our results show that MRI can be used to depict healthy and inflamed mouse colon and that the T2w signal, contrast‐enhanced T1w signal, and colon wall thickness may be used to characterize inflammation in experimental colitis. These potential biomarkers may be useful in the evaluation of putative drugs in longitudinal studies in both mice and humans.

Repeated Three-Dimensional Magnetic Resonance Imaging of Atherosclerosis Development in Innominate Arteries of Low-Density Lipoprotein Receptor-Knockout Mice

Background—In vivo methods to evaluate the size and composition of atherosclerotic lesions in animal models of atherosclerosis would assist in the testing of antiatherosclerotic drugs. We have developed an MRI method of detecting atherosclerotic plaque in the major vessels at the base of the heart in low-density lipoprotein (LDL) receptor-knockout (LDLR−/−) mice on a high-fat diet. Methods and Results—Three-dimensional fast spin-echo magnetic resonance images were acquired at 7 T by use of cardiac and respiratory triggering, with ≈140-&mgr;m isotropic resolution, over 30 minutes. Comparison of normal and fat-suppressed images from female LDLR−/− mice 1 week before and 8 and 12 weeks after the transfer to a high-fat diet allowed visualization and quantification of plaque development in the innominate artery in vivo. Plaque mean cross-sectional area was significantly greater at week 12 in the LDLR−/− mice (0.14±0.086 mm2 [mean±SD]) than in wild-type control mice on a normal diet (0.017±0.031 mm2, P <0.01). In the LDLR−/− mice, but not control mice, increase in plaque burden at week 12 relative to week 1 was also highly significant (P =0.001). Lumen cross section was not significantly different between time points or groups. MRI and histological assessments of plaque size were closely correlated (R =0.8). The lumen of proximal coronary arteries could also be visualized. Conclusions—This is the first report of in vivo detection of aortic arch atherosclerosis in any animal model. The method could significantly assist rapid evaluation of experimental antiatherosclerotic therapies.

Measurement of MR signal and T2* in lung to characterize a tight skin mouse model of emphysema using single-point imaging

To evaluate whether MRI signal and T2* measurements of lung tissue acquired at ultrashort detection times (tds) can detect emphysematous changes in lungs.

Automatic segmentation of intra‐abdominal and subcutaneous adipose tissue in 3D whole mouse MRI

To fully automate intra‐abdominal (IAT) and total adipose tissue (TAT) segmentation in mice to replace tedious and subjective manual segmentation.

Assessment of gadoxetate DCE-MRI as a biomarker of hepatobiliary transporter inhibition

Drug‐induced liver injury (DILI) is a clinically important adverse drug reaction, which prevents the development of many otherwise safe and effective new drugs. Currently, there is a lack of sensitive and specific biomarkers that can be used to predict, assess and manage this toxicity. The aim of this work was to evaluate gadoxetate‐enhanced MRI as a potential novel biomarker of hepatobiliary transporter inhibition in the rat. Initially, the volume fraction of extracellular space in the liver was determined using gadopentetate to enable an estimation of the gadoxetate concentration in hepatocytes. Using this information, a compartmental model was developed to characterise the pharmacokinetics of hepatic uptake and biliary excretion of gadoxetate. Subsequently, we explored the impact of an investigational hepatobiliary transporter inhibitor on the parameters of the model in vivo in rats. The investigational hepatobiliary transporter inhibitor reduced both the rate of uptake of gadoxetate into the hepatocyte, k1, and the Michaelis–Menten constant, Vmax, characterising its excretion into bile, whereas KM values for biliary efflux were increased. These effects were dose dependent and correlated with effects on plasma chemistry markers of liver dysfunction, in particular bilirubin and bile acids. These results indicate that gadoxetate‐enhanced MRI provides a novel functional biomarker of inhibition of transporter‐mediated hepatic uptake and clearance in the rat. Since gadoxetate is used clinically, the technology has the potential to provide a translatable biomarker of drug‐induced perturbation of hepatic transporters that may also be useful in humans to explore deleterious functional alterations caused by transporter inhibition. Copyright

Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction

The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined. These decisions are complicated by the array of imaging techniques, which have varying sensitivities, specificities, availabilities, local expertise, safety, and costs, and by the variable time-course of tissue damage, functional myocardial depression, or recovery of function. This White Paper summarizes scientific discussions of members of the Cardiac Safety Research Consortium on the main factors to consider when selecting nonclinical and clinical cardiac function imaging techniques in drug development. We focus on 3 commonly used imaging modalities in the evaluation of cardiac function: echocardiography, magnetic resonance imaging, and radionuclide (nuclear) imaging and highlight areas for future research.

(1)H and hyperpolarized (3)He MR imaging of mouse with LPS-induced inflammation

To evaluate the lipopolysaccharide (LPS) model of chronic obstructive pulmonary disease (COPD) in mouse with 1H and hyperpolarized (HP) 3He MR imaging.

Accurate T-1 Mapping for Oxygen-Enhanced MRI in the Mouse Lung Using a Segmented Inversion-Recovery Ultrashort Echo-Time Sequence

A segmented inversion‐recovery module combined with the 2D ultrashort echo time radial technique is proposed that allows accurate pixel level T1 mapping of mouse lung in vivo.

COPD Patients Have Short Lung Magnetic Resonance T1 Relaxation Time.

Abstract Magnetic resonance imaging (MRI) may provide attractive biomarkers for assessment of pulmonary disease in clinical trials as it is free from ionizing radiation, minimally invasive and allows regional information. The aim of this study was to characterize lung MRI T1 relaxation time as a biomarker of chronic obstructive pulmonary disease (COPD); and specifically its relationship to smoking history, computed tomography (CT), and pulmonary function test (PFT) measurements in comparison to healthy age-matched controls. Lung T1 and inter-quartile range (IQR) of T1 maps from 24 COPD subjects and 12 healthy age-matched non-smokers were retrospectively analyzed from an institutional review board approved study. The subjects underwent PFTs and two separate MR imaging sessions at 1.5 tesla to test T1 repeatability. CT scans were performed on the COPD subjects. T1 repeatability (intraclass correlation coefficient) was 0.72 for repeated scans acquired on two visits. The lung T1 was significantly shorter (p < 0.0001) and T1 IQR was significantly larger (p = 0.0002) for the COPD subjects compared to healthy controls. Lung T1 significantly (p = 0.001) correlated with lung density assessed with CT. Strong significant correlations (p < 0.0001) between lung T1 and all PFT measurements were observed. Cigarette exposure did not correlate with lung T1 in COPD subjects. In conclusion, lung MRI T1 mapping shows potential as a repeatable, radiation free, non-invasive imaging technique in the evaluation of COPD.