INVESTIGATION OF GADOLINIUM CONTRAST AGENT TOXICITY BY XAS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 由于它们的顺磁性，有机Gd配合物和Gd化合物的溶液被用作静脉注射放射造影剂，以增强医学磁共振成像中的图像。多年来，美国、欧洲和日本的成年人和儿童一直在使用Gd，数千名患者没有出现任何严重的并发症。美国食品和药物管理局于1988年宣布，用于核磁共振的钆是安全的。然而，可能会出现一些副作用，如轻微的头痛、恶心和局部灼热。Caravan和他的同事最近发现，严重肾功能障碍的患者如果进行了基于Gd的磁共振对比剂，就容易患上“肾源性全身性纤维化”。他们的结果表明，在人类受试者中，Gd在肾脏和心脏中特别丰富。对Gd如何与这些组织相互作用的基本了解将对确定这些患者Gd毒性的分子来源至关重要。我们认为，使用XANES和EXAFS测量心脏和肾脏组织中的Gd是这一独特的实验机会最合适的第一步，这可能会对翻译研究产生重大影响。我们希望从尸检样本中确定Gd在组织中的局部配位环境，并将这些结果与可能的生物Gd模型进行比较，如Gd磷酸盐、Gd硫酸盐和有机Gd造影剂。根据这些数据，我们将能够清楚地确定Gd造影剂是否以及如何在肾脏和心脏组织中发生化学变化。Gd配位和/或氧化态的变化可能会导致在大篷车实验室观察到的不利影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Because of their paramagnetic properties, solutions of organic gadolinium complexes and gadolinium compounds are used as intravenous radiocontrast agents to enhance images in medical magnetic resonance imaging. Gadolinium has been used for years in adults and children in the United States, Europe and Japan, without any serious complications in thousands of patients. The FDA declared Gadolinium safe for use in MRI in 1988. However, a few side effects, such as mild headache, nausea and local burning can occur. Caravan and colleagues have recently found that patients with severe kidney dysfunction are susceptible to "nephrogenic systemic fibrosis" if they get gadolinium based MR contrast. Their results indicate that in human subjects, Gd is particularly rich in the kidney and heart. A fundamental understanding of how Gd interacts with these tissues will be crucial in determining the molecular origin of Gd toxicity in these patients. We believe that surveying Gd in regions of heart and kidney tissue using XANES and EXAFS is the most appropriate first step in this unique experimental opportunity, which could potentially have a large impact on translational research. We wish to determine the local coordination environment of Gd in tissue from autopsy samples and compare these results to likely biological Gd models, such as Gd phosphate, Gd sulfate, and the organic Gd contrast agent. From these data, we will be able to clearly determine if and how the Gd contrast agent is chemically altered in kidney and heart tissue. Changes in Gd coordination and/or oxidation state could potentially lead to the adverse effects observed in the Caravan lab.