Nephrogenic Systemic Fibrosis (NSF): A Rodent Model for Therapeutic Intervention

肾源性系统性纤维化（NSF）：用于治疗干预的啮齿动物模型

基本信息

批准号：
8225182
负责人：
Wassana Yantasee
金额：
$ 45.24万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-10 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225182
关键词：
Adenine Affect Animal Model Animals Bioinorganic Chemistry Blood Boxing Chemical Structure Chronic Kidney Failure Collaborations Complex Contrast Media Dependency Dermatopathology Development Diagnostic Dialysis procedure Disease Dose Drug Kinetics Excision Exposure to Fibrosis Foundations Gadolinium Health Health Sciences Hemodialysis Human Image Imaging Techniques Impairment Incidence Indigenous Inorganic Chemistry Kidney Kidney Failure Laboratories Link Magnetic Resonance Imaging Medical Medicine Metals Methods Mission Modeling Morbidity - disease rate National Institute of General Medical Sciences Nephrology Oregon Organ Organism Pacific Northwest Patients Positioning Attribute Prevention Prevention approach Rattus Renal function Reporting Research Research Personnel Research Support Resolution Risk Rodent Model Silicon Dioxide Subcutaneous Tissue Therapeutic Therapeutic Intervention Tissues Transplant Recipients Universities Work base chronic liver disease disease diagnosis effective therapy gadolinium oxide improved innovation liver transplantation metal chelator metal complex mortality novel prevent public health relevance radiologist treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): This R01 proposal focuses on a new emerging disease, Nephrogenic Systemic Fibrosis (NSF), which affects patients with severe renal impairment. NSF is a progressive, debilitating disease with increased morbidity and mortality and has been linked to exposure to gadolinium (Gd) based contrast agents used in Magnetic Resonance Imaging (MRI). The 2007 FDA's box warning regarding the risk of all gadolinium-based contrast agents in developing NSF may affect a large number of patients (e.g., an estimated 27.5 million MRI procedures were performed in 2007 in the U.S. alone and 43 percent used Gd based contrast agents as part of the imaging procedure). At present, radiologists are hesitant to administer any type of Gd based contrast agents to patients with any level of renal impairment, which makes it difficult for clinicians to obtain high resolution imaging for patients with renal insufficiency. Few studies have relied on animal models to study how Gd based contrast agents trigger NSF, but rats with normal kidney function used in the studies fail to represent patients with renal failure, a pre-existing condition for most NSF cases. Currently, there is no effective treatment for NSF, thus the only recommended action is hemodialysis to remove the Gd contrast agent from the blood. However, proof of hemodialysis efficacy is lacking. Our proposed work is innovative because it will utilize a chronic renal failure (CRF) rat model to study NSF that is triggered by Gd based contrast agents, followed by applying our new decorporation method based on advanced functional materials to remove the Gd contrast agent from the animals. Specifically, once the chronic renal failure (CRF) rat model is produced by adenine dosing, NSF disease in these animals will be studied as a function of dose-dependency and chemical structures of Gd based contrast agents as well as involvement of other indigenous metals. Pharmacokinetics of the Gd based contrast agent will be studied in order to optimize the removal strategies by both novel decorporation and hemodialysis methods. The efficacy of both methods will be assessed in terms of the reduction of blood and tissue Gd content and the prevention of NSF incidence in the animals. This research is directly responsive to PA-08-251: Metals in Medicine, since it involves "the interactions of synthetic inorganic complexes with living systems and their components" as well as "diagnostic and therapeutic applications of metal complexes and of metal chelators." Through the collaboration among leading inorganic chemists, physicist, and toxicologist at the Pacific Northwest National Laboratory (PNNL) and experts in dermatopathology and nephrology at the Oregon Health & Science University (OHSU), our research team is uniquely capable of studying both NSF mechanism and prevention approaches. The propose work also aligns well with the mission of National Institute of General Medical Sciences (NIGMS), which is "Supporting research that is the foundation for disease diagnosis, treatment, and prevention." PUBLIC HEALTH RELEVANCE: This project aims at understanding how a new emerging disease, Nephrogenic Systemic Fibrosis (NSF), is triggered by gadolinium (Gd) based contrast agents used in Magnetic Resonance Imaging (MRI), and how to effectively prevent it with a novel blood decorporation method, thus allowing for the continued use of Gd based contrast MRI in patients with renal insufficiency.

描述（由申请人提供）：该 R01 提案重点关注一种新出现的疾病，即肾源性系统性纤维化 (NSF)，该疾病影响严重肾功能不全的患者。 NSF 是一种进行性、使人衰弱的疾病，发病率和死亡率增加，与接触磁共振成像 (MRI) 中使用的钆 (Gd) 造影剂有关。 2007 年 FDA 对所有钆基造影剂在发生 NSF 时的风险发出框警告，可能会影响大量患者（例如，估计 2007 年仅在美国就进行了 2750 万次 MRI 手术，其中 43% 使用钆基造影剂作为成像过程的一部分）。目前，放射科医生对于是否对任何程度的肾功能不全患者使用任何类型的钆基造影剂都犹豫不决，这使得临床医生很难获得肾功能不全患者的高分辨率成像。很少有研究依赖动物模型来研究基于钆的造影剂如何引发 NSF，但研究中使用的肾功能正常的大鼠无法代表肾衰竭患者，而肾衰竭是大多数 NSF 病例的既往病症。目前，NSF没有有效的治疗方法，因此唯一推荐的措施是血液透析以去除血液中的Gd造影剂。然而，缺乏血液透析功效的证据。我们提出的工作具有创新性，因为它将利用慢性肾功能衰竭（CRF）大鼠模型来研究由基于 Gd 的造影剂触发的 NSF，然后应用我们基于先进功能材料的新装饰方法从模型中去除 Gd 造影剂。动物。具体来说，一旦通过腺嘌呤给药产生慢性肾衰竭 (CRF) 大鼠模型，这些动物中的 NSF 疾病将被研究为基于 Gd 的造影剂的剂量依赖性和化学结构以及其他本土金属的参与的函数。将研究基于 Gd 的造影剂的药代动力学，以便通过新型去离子和血液透析方法优化去除策略。两种方法的功效将从血液和组织 Gd 含量的降低以及动物 NSF 发病率的预防方面进行评估。这项研究直接响应 PA-08-251：医学中的金属，因为它涉及“合成无机配合物与生命系统及其成分的相互作用”以及“金属配合物和金属螯合剂的诊断和治疗应用”。通过太平洋西北国家实验室 (PNNL) 领先的无机化学家、物理学家和毒理学家与俄勒冈健康与科学大学 (OHSU) 皮肤病理学和肾脏病学专家之间的合作，我们的研究团队具有独特的能力来研究 NSF 机制和预防方法。这项拟议的工作也与国家普通医学科学研究所 (NIGMS) 的使命非常契合，即“支持作为疾病诊断、治疗和预防基础的研究”。公共健康相关性：该项目旨在了解磁共振成像 (MRI) 中使用的基于钆 (Gd) 的造影剂如何引发一种新出现的疾病——肾源性系统性纤维化 (NSF)，以及如何使用新型药物有效预防该疾病。血液装饰方法，从而允许在肾功能不全患者中继续使用基于 Gd 的对比 MRI。