Phosphorus-31 MR Spectroscopic Imaging and Fingerprinting

2型糖尿病（T2D）是一种影响全球大量人群的流行疾病。新兴 有证据表明，受损的肌肉代谢在T2D的发病机制中起主要作用。 正常化线粒体功能已被提出作为T2D的有效治疗靶点。 Phophorus-31（31P）磁共振波谱和成像（MRS/I）方法提供了一个强大的 这是一个研究组织代谢各个方面的工具。具体地，31P MRS可以直接监测 在生理和病理过程中磷酸盐代谢物浓度的变化， 如运动和缺血/再灌注。此外，磁化转移（MT）方法允许 非侵入性定量代谢活动，没有其他方法能够。这些方法 具有转化为临床应用的潜力， 在某些实施方案中，所述代谢指示疾病进展和治疗功效。但因为 低浓度的磷酸盐代谢产物，目前的31P MRS/I方法需要非常长的时间， 采集时间，这对于常规临床使用是不实际的。因此，大多数31P MRS研究 采用非局部或单体素技术，对代谢的评估 异质性是不可能的 稀疏采样理论和子空间成像的最新发展已经证明了其潜力 通过显着减少质子（1H）MRSI的采集时间。此外，创新带来的 通过磁共振指纹（MRF）已被证明可以大大加速1H的映射 大脑的放松时间。基于这些令人兴奋的进展，我们建议翻译这些1H MRSI， 方法开发临床可行的31 P MRS/I方法，用于体内评估线粒体 糖尿病肌肉的功能。该项目的目标是：1）开发31 P空间光谱 具有（k，t）-空间稀疏采样的编码方法，用于高加速代谢映射， 磷酸盐代谢物; 2）开发31P光谱MT-MRF方法，用于有效定量 ATP和PCr合成速率。这些方法将被应用于描绘代谢的改变， Zucker糖尿病肥胖大鼠（肥胖和胰岛素的大鼠模型）中的通量和线粒体氧化能力 阻力此外，运动训练和二甲双胍治疗的效果， 还将评估T2D治疗对肌肉代谢的影响。成功完成本 该项目将为评估体内线粒体能量学铺平道路。虽然目前的项目将 采用啮齿类动物模型的T2D为节省成本的目的，提出的31 P MRSI和MRF方法 高度可转换为临床扫描仪，这将导致临床可行和相关的诊断， 以及评估代谢疾病谱的治疗功效的新策略。

Type 2 diabetes (T2D) is a prevalent disease affecting a large population worldwide. Emerging evidence suggests that impaired muscle metabolism plays a major role in the pathogenesis of T2D. Normalizing mitochondrial function has be proposed as an effective therapeutic target for T2D. Phophorus-31 (31P) magnetic resonance spectroscopy and imaging (MRS/I) methods provide a powerful tool to interrogate various aspects of tissue metabolism. Specifically, 31P MRS can directly monitor changes in phosphate metabolite concentrations during physiological and pathological processes such as exercise and ischemia/reperfusion. Furthermore, magnetization-transfer (MT) methods allows noninvasive quantification of metabolic activities that no other methods are capable of. These methods have the potential to be translated to clinical use that will permit noninvasive evaluation of tissue metabolism that is indicative of disease progression and therapeutic efficacy. However, because of the low concentrations of phosphate metabolites, current 31P MRS/I methods require prohibitively long acquisition time, which is not practical for routine clinical use. Consequently, most 31P MRS studies have employed either non-localized or single voxel techniques, rendering the assessment of metabolic heterogeneity impossible. Recent development in sparse sampling theory and subspace imaging have demonstrated potential by significantly reducing acquisition time for proton (1H) MRSI. Furthermore, the innovation brought forth by magnetic resonance fingerprinting (MRF) has been shown to drastically accelerate the mapping of 1H relaxation times in the brain. Based on these exciting progress, we propose to translate these 1H MRSI approaches to develop clinically feasible 31P MRS/I methods for in vivo assessment of mitochondrial function in diabetic muscle. The objectives of the proposed project are: 1) to develop 31P spatiospectral encoding method with sparse sampling of the (k, t)-space for highly accelerated metabolic mapping of phosphate metabolites; 2) to develop 31P spectroscopic MT-MRF methods for efficient quantification of ATP and PCr synthesis rates. These methods will be applied to delineate the alterations in metabolic fluxes and mitochondrial oxidative capacity in Zucker diabetic fatty rats, a rat model of obesity and insulin resistance. In addition, the effects of exercise training and metformin treatment, the commonly prescribed treatment for T2D, on muscle metabolism will also be evaluated. The successful completion of this project will pave the way for evaluating mitochondrial energetics in vivo. While the current project will employ a rodent model of T2D for the purpose of cost-saving, the proposed 31P MRSI and MRF methods are highly translatable to clinical scanners, which will lead to clinically feasible and relevant diagnostics, as well as novel strategies to assess the therapeutic efficacy for a spectrum of metabolic diseases.