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

• 批准号: 7768481
• 负责人: Wassana Yantasee
• 金额: $ 44.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 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/7768481
• 关键词: Adenine; Affect; Animal Model; Animals; Bioinorganic Chemistry; Blood; Boxing; Chemical Structure; Chronic; 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; Liver diseases; 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; disease diagnosis; effective therapy; improved; innovation; liver transplantation; metal chelator; metal complex; mortality; novel; prevent; public health relevance; radiologist; treatment strategy; uptake

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）：本R 01提案重点关注一种新发疾病--肾源性系统性纤维化（NSF），该疾病影响重度肾损害患者。NSF是一种进行性、使人衰弱的疾病，发病率和死亡率增加，与暴露于磁共振成像（MRI）中使用的钆（Gd）造影剂有关。2007年FDA关于所有钆基造影剂在开发NSF中的风险的警告框可能会影响大量患者（例如，2007年仅在美国就进行了估计2750万次MRI程序，43%使用基于Gd的造影剂作为成像程序的一部分）。目前，放射科医生不愿对任何级别的肾损害患者施用任何类型的Gd基造影剂，这使得临床医生难以获得肾功能不全患者的高分辨率成像。很少有研究依赖于动物模型来研究基于Gd的造影剂如何触发NSF，但是研究中使用的肾功能正常的大鼠不能代表肾衰竭患者，肾衰竭是大多数NSF病例的预先存在的疾病。目前，对于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从血液中去除Gd造影剂。然而，缺乏血液透析有效性的证据。我们提出的工作是创新的，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的去离子方法来去除动物体内的Gd造影剂。具体而言，一旦通过腺嘌呤给药产生慢性肾衰竭（CRF）大鼠模型，将研究这些动物中的NSF疾病与Gd造影剂的剂量依赖性和化学结构以及其他固有金属的关系。将研究Gd基造影剂的药代动力学，以优化通过新的脱钙和血液透析方法的清除策略。将根据血液和组织Gd含量的降低以及动物中NSF发生率的预防来评估两种方法的有效性。该研究直接响应PA-08-251：医学中的金属，因为它涉及“合成无机络合物与生命系统及其组分的相互作用”以及“金属络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以及俄勒冈州健康与科学大学（OHSU）的皮肤病理学和肾脏学专家之间的合作，我们的研究团队能够独特地研究NSF机制和预防方法。这项工作也与国立综合医学科学研究所（NIGMS）的使命相一致，即“支持作为疾病诊断、治疗和预防基础的研究”。" 公共卫生关系：本项目旨在了解磁共振成像（MRI）中使用的钆（Gd）造影剂如何触发一种新出现的疾病--肾源性系统性纤维化（NSF），以及如何通过一种新的血液净化方法有效预防，从而允许在肾功能不全患者中继续使用钆造影剂MRI。