Magnetic Resonance Imaging and Spectroscopy of Rodent Models of Disease

I)一个项目涉及对成骨不全小鼠模型的皮肤进行分析。这是因为诊断中重度成骨不全(OI)具有侵入性且耗时。然而，如果OI的I型胶原异常在皮肤中明显存在，MRI将是一种潜在的诊断方法。因此，我们使用MRI来检测OIM/OIM和OIM/+小鼠的皮肤异常：这是OI的小鼠模型。正常小鼠和OIM/OIM小鼠之间的差异包括引入了真皮下发现的毛囊丰富层(层2L)。MRI结果也与胶原含量降低和更高水合的胶原网络相一致。人类胎儿组织的组织学研究表明，这些皮肤变化也可能出现在OI患者身上。我们的结论是，用MRI表征OIM/OIM和OIM/+小鼠皮肤的表型差异是可行的，并有可能扩展到人类OI的诊断。 Ii)(与Nikolai Soldatov)的其他工作集中在过度表达钙通道的α-1C22+剪接变体的转基因小鼠(TG++)的心血管功能分析上。用核磁共振成像(MRI)研究基础状态和异丙肾上腺素(IP)应激7d以上时的心血管表型。慢性IP应激显著增加野生型(WT)和TG22+/+小鼠的左心室(LV)质量和LV/体重比。此外，与赋形剂治疗组相比，正常组和TG22+/+组的LV收缩末期容量(EDV)显著增加。此外，在TG22+/+小鼠中，ip诱导的应激显著降低了LV射血分数和心输出量。总体而言，TG22+/+小鼠的慢性IP应激导致的收缩功能障碍明显大于WT小鼠，这表明对β-肾上腺素能应激的反应增加了重构。这一观察可能为该通道在心血管疾病中的潜在致病作用提供了洞察力。 3)(与大卫·威尔逊)脑的磁共振波谱是形态成像研究的极好的辅助工具。我们使用这种方法来定义XRCC1缺陷(KO)小鼠的小脑代谢物，在KO小鼠中，这个碱基切除修复和单链断裂修复的关键参与者是缺失的。进行了磁共振成像和光谱分析。在成像实验中，两组的小脑体积没有差异。在光谱学实验中，我们能够使用TE=135ms编辑脂质信号，从而清晰地描绘胆碱、肌酸和NAA。NAA神经元标志物在两组间差异无统计学意义。对于核磁共振体积测量和神经元活性的磁共振光谱测量，在XRCC1 KO动物中可以看到数据的更大变异性。总体而言，尽管XRCC1 KO表型显示了小脑性共济失调，但我们发现正常动物和KO动物在小脑体积或小脑神经元活性方面没有差异。因此，尽管保留了这些重要的脑表型参数，共济失调表型仍然存在。我们将继续改进我们的技术，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 mildly severe 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) (With Nikolai Soldatov) 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) (with David Wilson) 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!