Magnetic Resonance Imaging and Spectroscopy of Rodent Models of Disease

i）一个项目涉及分析骨生成的小鼠模型中的皮肤。 这是因为轻度成骨不全（OI）的诊断是侵入性的，而且耗时。然而，如果OI的I型胶原异常在皮肤中表现出来，MRI将是一种潜在的诊断方法。因此，我们使用MRI检测oim/oim和oim/+小鼠的皮肤异常：这些是OI的小鼠模型。 正常和oim/oim小鼠之间的差异包括在真皮下发现的毛囊丰富层（层2L）的引入。MRI结果也与胶原蛋白含量降低和更高度水合的胶原蛋白网络一致。人类胎儿组织的组织学表明，这些皮肤变化也可能在患有OI的人类患者中表现出来。我们的结论是，表征的表型差异，在皮肤的oim/oim和oim/+小鼠的MRI是可行的，并可能扩展到人类OI的诊断。 ii）额外的工作集中在分析过表达钙通道的α-1C 22 ++剪接变体的转基因小鼠（TG++）的心血管功能上。 磁共振成像（MRI）被用来研究心血管表型在基础状态，以及在应激诱导的异丙肾上腺素（IP）输注超过7天。慢性IP应激显著增加了野生型（WT）和TG 22 +/+小鼠的左心室（LV）质量和LV与体重的比值。此外，与溶剂处理的小鼠相比，正常小鼠和TG 22 +/+小鼠的LV收缩末期容积（EDV）均显著升高。此外，TG 22 +/+小鼠中IP诱导的应激显着降低了LV射血分数和心输出量。 总体而言，TG 22 +/+小鼠的慢性IP应激导致的收缩功能障碍明显大于WT，表明响应于β-肾上腺素能应激的重塑增加。这一观察结果可能为该通道在心血管疾病中的潜在致病作用提供见解。 iii）脑的MR波谱是形态学成像研究的极好辅助。 我们使用这种方法来定义XRCC 1缺陷（KO）小鼠的小脑代谢物，其中缺乏碱基切除修复和单链断裂修复的关键参与者。进行了MR成像和光谱分析。 在成像实验中，发现两组之间的小脑体积没有差异。 在光谱实验中，我们能够通过使用TE = 135 ms编辑脂质信号，从而允许清楚地描绘胆碱、肌酸和NAA。 两组间NAA神经元标记物无差异。 对于神经元活力的MRI体积测量和MR光谱测量，在XRCC 1 KO动物中观察到数据的较大变异性。 总体而言，尽管小脑共济失调表现在XRCC 1 KO表型，我们发现正常和KO动物之间的小脑体积或小脑神经元活力没有差异。因此，共济失调表型是存在的，尽管保存这些重要的参数的脑表型。 我们将继续完善我们的技术，并将其应用于其他疾病模型，如亨廷顿舞蹈病。

i) One project involves the analysis of skin in a mouse model of osteogenesis imperfecta. This is motivated by the fact that diagnosis of mild osteogenesis imperfecta (OI) is invasive and time consuming. However, if the type I collagen abnormalities of OI are manifest in skin, MRI would represent a potential diagnostic approach. Accordingly, we used MRI to detect dermal abnormalities in oim/oim and oim/+ mice: these are mice models for OI. Differences between normal and oim/oim mice included the introduction of a hair follicle-rich layer (layer 2L) found below the dermis. MRI results were also consistent with decreased collagen content and a more highly hydrated collagen network. Histology of human fetal tissue indicated that these skin changes may also be manifest in human patients with OI. We conclude that characterization of phenotypic differences in the skin of oim/oim and oim/+ mice by MRI is feasible, and may potentially be extended to diagnosis of human OI. ii) Additional work centers on analysis of cardiovascular function in transgenic mice (TG++) overexpressing the alpha-1C22++ splice variant of a calcium channel. Magnetic resonance imaging (MRI) was used to investigate the cardiovascular phenotype in the basal state, as well as during stress induced by isoproterenol (IP) infusion over 7 days. Chronic IP stress significantly increased left ventricle (LV) mass and LV to body weight ratio in both wild type (WT) and TG22+/+ mice. In addition, LV end-systolic volume (EDV) in both normal and TG22+/+ were significantly elevated compared to vehicle-treated mice. Further, IP-induced stress in TG22+/+ mice significantly decreased LV ejection fraction and cardiac output. Overall, chronic IP stress in TG22+/+ mice resulted in markedly greater contractile dysfunction than in WT, indicating increased remodeling in response to beta-adrenergic stress. This observation may provide insight into a potential pathogenic role for this channel in cardiovascular disease. iii) MR spectroscopy of brain is an excellent adjunct to morphologic imaging studies. We use this approach to define cerebellar metabolites in the XRCC1-deficient (KO) mouse, in which this key participant in base excision repair and single-strand break repair is lacking. Both MR imaging and spectroscopic analyses were performed. In the imaging experiments, cerebellar volume was found not to differ between the two groups. In the spectroscopy experiments, we were able to edit lipid signal by use of a TE = 135 ms, permitting clear delineation of choline, creatine, and NAA. No difference in the NAA neuronal marker was observed between the two groups. For both MRI volume measurements and MR spectroscopic measurements of neuronal viability, a larger variability in the data was seen in the XRCC1 KO animals. Overall, in spite of the cerebellar ataxia demonstrated in the XRCC1 KO phenotype, we found no differences in cerebellar volume or in cerebellar neuronal viability between the normal and KO animals. Thus, the ataxic phenotype is present in spite of preservation of these important parameters of brain phenotype. We will continue to refine our techniques and apply them to other disease models, such as Huntington's Chorea.