Assessing Mitochondrial Metabolism using 31P Magnetic Resonance Fingerprinting

描述(由申请人提供)：由缺血-再灌注(IR)损伤引起的心肌细胞死亡是美国发病率和死亡率的主要原因。越来越多的证据表明，线粒体通透性转换孔(MPTP)这一非特异性线粒体膜电导通道的开放是IR损伤的关键因素。MPTP开放的一个效应是质子通过线粒体内膜泄漏，使线粒体氧化与ATP合成解偶联，加剧先前存在的ATP赤字。在急性缺血事件中，药物抑制MPTP是一种很有前途的心脏保护策略。然而，缺乏有效的非侵入性方法来研究体内线粒体的功能，限制了对IR损伤机制的了解，以及新疗法的开发。磷-31(31P)磁共振波谱(MRS)是解决这一需求的一种有吸引力的方法。31P磁化转移谱(MT-MRS)长期以来一直被认为是测量体内ATP合成速率的一种手段。结合31P MT-MRS和耗氧率的测量，可以评估线粒体的偶联。然而，目前的31P MT-MRS方法需要非常长的成像时间才能准确地测量ATP合成速率。另一方面，最近发展起来的磁共振指纹(MRF)方法为磁共振数据采集提供了一个全新的框架，允许同时高速测量包括弛豫时间在内的多个组织属性。MT-MRS中化学交换通量的测量与MR成像中弛豫时间的测量高度相似。因此，本提案的总体目标是开发和验证快速新颖的31P磁共振波谱指纹(MRSF)技术来定量测量ATP合成速率。这个项目有两个具体目标。目的1包括三个部分：通过计算机模拟开发31P磁共振波谱方法，在体模实验中实现所开发的方法，以及在不同负荷下在灌流心脏中验证31P磁共振波谱方法与已建立的31P MT-MRS方法。在目标2中，将进一步评估所开发的31P MRSF方法在有或没有MPTP药物抑制的大鼠全脑缺血再灌注损伤模型中的实用性。这些实验结果将有助于阐明MPTP抑制诱导IR心脏保护的机制。此外，成功的方法开发将为临床可行的相关诊断以及代谢紊乱谱的纵向研究铺平道路。

DESCRIPTION (provided by applicant): Myocardial cell death induced by ischemia-reperfusion (IR) injury is a major cause of morbidity and mortality in the US. Mounting evidence suggests that the opening of a nonspecific inner mitochondrial membrane conductance channel, the mitochondrial Permeability Transition Pore (mPTP), is a key factor of IR injury. One effect of mPTP opening is the leakage of protons across the inner mitochondrial membrane, which uncouples mitochondrial oxidation from ATP synthesis and exacerbates the preexisting ATP deficit. Pharmacological inhibition of mPTP is a promising strategy for cardio protection in acute ischemic events. However, the lack of effective noninvasive methods to study mitochondrial function in vivo limits the understanding of IR injury mechanisms, as well as the development of novel therapeutics. Phosphorus-31 (31P) Magnetic Resonance Spectroscopy (MRS) is an attractive method to address this need. 31P Magnetization Transfer spectroscopy (MT-MRS) has long been proposed as a means of measuring ATP synthesis rates in vivo. Combination of 31P MT-MRS with the measurement of oxygen consumption rates allows the assessment of mitochondrial coupling. However, current 31P MT-MRS methods require prohibitively long imaging time to accurately measure ATP synthesis rates. On the other hand, recent development of Magnetic Resonance Fingerprinting (MRF) method provides a completely new framework for Magnetic Resonance data acquisition that allows simultaneous measurement of several tissue properties, including relaxation times, at high speed. The measurement of chemical exchange flux in MT-MRS is highly analogous to the measurement of relaxation times in MR imaging. Therefore, the overall objective of this proposal is to develop and validate fast novel 31P Magnetic Resonance Spectroscopy Fingerprinting (MRSF) technique to quantitatively measure ATP synthesis rate. This project has two specific aims. Aim 1 has three parts: developing 31P MRSF methods by computer simulation, implementing the developed methods in phantom experiments, and validating 31P MRSF methods against established 31P MT-MRS methods in perfused hearts under varying workloads. In Aim 2, the utility of the developed 31P MRSF method will be further assessed in a rat model of global IR injury, with and without pharmacological inhibition of mPTP. The results of these proposed experiments will help elucidate the mechanisms of mPTP inhibition induced cardio protection in IR. Furthermore, successful method development will pave the way for clinically feasible and relevant diagnostics as well as longitudinal studies of a spectrum of metabolic disorders.