Magnetic Resonance Chemical Exchange Saturation Transfer Imaging of Intracellular pH

本研究计划的总体目标是开发新的磁共振成像（MRI）方法来绘制生物体的组织pH值。组织pH值调节许多细胞过程，在正常情况下受到严格控制。因此，pH值是细胞功能障碍和窘迫的敏感指标，特别是当正常功能所需的氧气不足时。最近开发了几种方法来绘制生物体的pH值，具有高分辨率和灵敏度。例如，我的实验室以前开发了一种特定类型的MRI造影剂，可用于生成依赖于组织pH的图像对比度。我们发现，这些造影剂在溶液中可以很好地测量pH值，但在生物体中却不能有效地工作，因为检测灵敏度降低了。鉴于这一限制，我们最近开发了一种不同的方法来测量组织pH值，该方法使用相同类型的MRI对比，但源于组织中自然发现的信号。这种方法在体内测量pH值是有效的，但是，为了提高测量质量，实现这项技术的全部潜力，仍有许多挑战需要克服。我们将集中精力在三个方面提高图像质量。首先，我们将改进用于获取数据的MRI采集序列，以及用于建模和分析数据的拟合方法。具体来说，用于生成pH对比的MRI采集的持续时间很长，使得图像对采集过程中的运动和磁场波动非常敏感。我们将开发一种在采集过程中跟踪和校正运动和磁场波动的新方法。然后，我们将MRI信号响应的数学模型整合到数据分析中，以提高pH测量的精度。其次，我们将研究一组新的小分子，以确定它们是否可以在大脑中被检测到，使用与我们用来获得pH图相同的对比机制。利用现有的容易进入大脑的小分子可以让我们提高对pH依赖过程的敏感性。最后，我们将研究pH值测量与磁场强度和组织类型的关系。具体来说，我们将使用西方核磁共振扫描仪检查我们的方法在不同磁场强度（9.4特斯拉，7特斯拉和3特斯拉）下的工作效果。体内高分辨率组织pH图谱将提供有关生物体进化生物过程的新信息，为医学和制药工业的广泛应用铺平道路。

The overall goal of this research program is to develop novel magnetic resonance imaging (MRI) methods to map tissue pH in living organisms. Tissue pH regulates many cellular processes and is tightly controlled under normal conditions. Therefore, pH is a sensitive indicator of cellular dysfunction and distress, particularly when there is insufficient oxygen for normal function. Several methods have been developed recently to map pH in living organisms with high resolution and sensitivity. For example, my laboratory has previously developed a specific type of MRI contrast agent that can be used to generate image contrast that is dependent on tissue pH. We have found that these agents perform pH measurement well in solutions, but do not work as effectively in living organisms because detection sensitivity is reduced. Given this limitation, we have more recently developed a different method to measure tissue pH that uses the same type of MRI contrast but originates from signals found naturally in tissue. This method is effective at measuring pH in-vivo, however there remain a number of challenges to overcome to improve the quality of the measurements to realize the full potential of this technology. We will focus our efforts in three areas designed to improve image quality. First, we will make improvements to the MRI acquisition sequence used to acquire the data, and to the fitting methods used to model and analyze the data. Specifically, the duration of the MRI acquisition used to generate pH contrast is long making the images very sensitive to motion and magnetic field fluctuations during the acquisition.  We will develop a novel approach for the tracking and correction of motion and magnetic field fluctuations during the acquisition. Then we will incorporate our mathematical models of the MRI signal response into the analysis of the data to improve the precision of pH measurements. Second, we will examine a new set of small molecules to determine if they can be detected in the brain using the same contrast mechanism that we use to obtain pH maps. Using existing small molecules that cross easily into the brain could allow us to increase our sensitivity to pH dependent processes. Finally, we will study the dependence of the pH measurement on magnetic field strength and on tissue type. Specifically, we will examine how well our methods work at different magnetic field strengths (9.4 Tesla, 7 Tesla, and 3 Tesla) using MRI scanners that are available at Western. In-vivo high-resolution tissue pH mapping will provide new information about evolving biological processes in living organisms, paving the way for broad applications in medicine and the pharmaceutical industry.