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提案侧重于一种新的新兴疾病，肾病全身性纤维化（NSF），会影响严重的肾脏损害患者。 NSF是一种渐进的，使人衰弱的疾病，发病率和死亡率增加，与磁共振成像（MRI）中使用的基于Gadolinium（GD）的对比剂的暴露有关。 2007年FDA的盒子警告有关开发NSF的所有基于Gadolinium的对比剂的风险可能会影响大量患者（例如，仅在2007年，仅在美国就进行了2750万MRI程序，而43％的人使用GD基于GD的对比剂。作为成像程序的一部分）。目前，放射科医生不愿为具有任何水平的肾脏损害的患者管理任何类型的基于GD的对比剂，这使得临床医生很难为肾脏不足患者获得高分辨率成像。很少有研究依靠动物模型来研究基于GD的对比剂是如何触发NSF的，但是研究中使用的肾功能正常的大鼠无法代表肾衰竭的患者，这是大多数NSF病例的预先存在的疾病。当前，NSF没有有效的治疗方法，因此唯一建议的作用是从血液中去除GD对比剂的血液透析。但是，缺乏血液透析功效的证明。我们提出的工作具有创新性，因为它将利用慢性肾衰竭（CRF）大鼠模型来研究由基于GD的对比剂触发的NSF，然后使用基于先进功能材料的新装饰方法应用我们的新装饰方法，以从先进的功能材料中删除GD对比度。动物。具体而言，一旦通过腺嘌呤剂量产生慢性肾衰竭（CRF）大鼠模型，这些动物中的NSF疾病将作为剂量依赖性和基于GD的对比剂的化学结构的函数进行研究，以及其他土著金属的参与。将研究基于GD的对比剂的药代动力学，以通过新颖的装饰和血液透析方法来优化去除策略。两种方法的功效将根据血液和组织GD含量的减少以及预防动物的NSF发病率进行评估。这项研究直接响应PA-08-251：医学中的金属，因为它涉及“合成无机络合物与生物系统及其组件的相互作用”以及“金属络合物和金属螯合子的诊断和治疗应用”。通过Pacific Northwest国家实验室（PNNL）领先的无机化学家，物理学家和毒理学家之间的合作以及俄勒冈健康与科学大学（OHSU）皮肤病理学和肾脏病的专家，我们的研究团队具有独特的研究NSF机械机理和NSF机械机制和NSF机械机理和研究预防方法。这项建议的工作还与国家一般医学科学研究所（NIGMS）的使命良好，该研究所“支持疾病诊断，治疗和预防的基础研究”。公共卫生相关性：该项目旨在了解一种新的新兴疾病，肾病全身性纤维化（NSF）是由Gadolinium（GD）基于磁共振成像（MRI）触发的，以及如何用新颖的新颖性防止它。血液装饰方法，因此允许在肾脏功能不全的患者中继续使用基于GD的对比度MRI。