Molecular Imaging of Renal Fibrogenesis

肾纤维形成的分子成像

• 批准号: 8824746
• 负责人: Peter D Caravan
• 金额: $ 38.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824746
• 关键词: Accounting; Adriamycin PFS; Affinity; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Antibodies; Attenuated; Bilateral; Biochemical; Biopsy; Bone Marrow; Chronic Kidney Failure; Clinical Research; Collagen; Collagen Fibril; Creatinine; Data; Deposition; Detection; Dialysis procedure; Disease; Disease Progression; End stage renal failure; Enzymes; Extracellular Matrix Proteins; Fibrosis; Functional disorder; Genetically Engineered Mouse; Goals; Gold; Health; Hereditary nephritis; Image; In Vitro; Incidence; Kidney; Kidney Diseases; Kidney Transplantation; Lead; Libraries; Liver Fibrosis; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Medicare; Metals; Methodology; Methods; Modeling; Molecular; Monitor; Myofibroblast; Organ; Outcome; Pathway interactions; Patients; Process; Protein-Lysine 6-Oxidase; Pulmonary Fibrosis; Ramipril; Recovery; Renal function; Sampling Errors; Serum; Signal Transduction; Specificity; Time; Tissues; Toxic effect; United States; Ureteral obstruction; Urologic Diseases; base; crosslink; diagnosis standard; fibrogenesis; high risk; imaging modality; imaging probe; kidney cell; minimally invasive; molecular imaging; mouse model; novel; prototype; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): The goal of this proposal is to develop an effective magnetic resonance (MR) probe for noninvasive, molecular imaging of renal fibrosis. Renal fibrosis is a hallmark of all chronic kidney diseases (CKD). It is estimated that 500 million peopl worldwide are currently suffering from CKD and many of these patients will progress to end- stage renal disease (ESRD), a devastating disorder that requires dialysis or kidney transplantation. The incidence of ESRD has doubled over the last 25 years in the United States, and in fact, treatment of CKD and ESRD accounted for 27% ($60 billion) of Medicare expenses in 2005. Clinical studies have demonstrated a strong correlation between ESRD and the extent of renal fibrosis. Quantification of renal fibrosis should predict long-term outcome of renal function in CKD patients and could also be used to monitor response to new anti- fibrotic therapies. Currently, biopsy is the gold standard for diagnosing renal fibrosis. However, biopsy is not suitable for monitoring disease progression in CKD patients as it is invasive and subject to sampling error. Therefore, there is a major unmet medical need to develop noninvasive strategies to detect and monitor progression of renal fibrosis. This proposal is in response to RFA-DK-13-026, "Novel Methods for Detection and Measurement of Organ Fibrosis in Kidney, Bone Marrow, and Urological Diseases". In particular it responds to the specific need for "Novel minimally invasive imaging methods for the detection and measurement of organ fibrosis" and to "detect changes in fibrosis that quantify progression, stabilization, and/or regression over time" and to "Correlate fibrotic status with organ dysfunction, recovery, and/or regression" Renal function progressively declines in response to the excessive accumulation of extracellular matrix proteins. Myofibroblasts secrete collagens, as well as the enzyme lysyl oxidase (LOX) which crosslinks the collagen fibrils. Recently, we have developed a prototype small molecule magnetic resonance (MR) probe, termed Gd-Hyd, with specificity to cross-linked collagen. In preliminary data we have demonstrated that Gd- Hyd can accurately detect renal, liver and pulmonary fibrosis in small animal models. Since LOX-mediated crosslinking of collagen is an aspect of active disease, our hypothesis is that molecular imaging of LOX-mediated collagen crosslinking accurately reflects renal fibrogenesis and thus can be used to detect renal fibrosis and monitor disease progression and response to therapy. The importance of these studies cannot be overstated as CKD is a major worldwide health problem. The accomplishment of our Specific Aims would lead to a new methodology for identifying fibrotic patients at high- risk for disease progression and poor survival and also for monitoring response to anti-fibrotic therapies.

描述（由申请人提供）：本提案的目标是开发一种有效的磁共振（MR）探针，用于肾纤维化的无创分子成像。肾纤维化是所有慢性肾脏疾病（CKD）的一个标志。据估计，目前全世界有 5 亿人患有 CKD，其中许多患者将发展为终末期肾病 (ESRD)，这是一种需要透析或肾移植的破坏性疾病。过去 25 年中，美国 ESRD 的发病率翻了一番，事实上，2005 年 CKD 和 ESRD 的治疗费用占医疗保险费用的 27%（600 亿美元）。临床研究表明，ESRD 与终末期肾病之间存在很强的相关性。肾纤维化的程度。肾纤维化的量化应该可以预测 CKD 患者肾功能的长期结果，也可以用于监测新的抗纤维化疗法的反应。目前，活检是诊断肾纤维化的金标准。然而，活检不适合监测 CKD 患者的疾病进展，因为它是侵入性的并且容易受到 抽样误差。因此，开发非侵入性策略来检测和监测肾纤维化进展存在着未满足的重大医疗需求。 该提案是对 RFA-DK-13-026“肾脏、骨髓和泌尿系统疾病器官纤维化检测和测量的新方法”的回应。特别是，它满足了“用于检测和测量器官纤维化的新型微创成像方法”和“检测纤维化的变化，量化随时间的进展、稳定和/或消退”以及“关联纤维化状态”的具体需求。随着器官功能障碍、恢复和/或退化”肾功能因细胞外基质蛋白的过度积累而逐渐下降。肌成纤维细胞分泌胶原蛋白以及使胶原纤维交联的赖氨酰氧化酶（LOX）。最近，我们开发了一种原型小分子磁共振 (MR) 探针，称为 Gd-Hyd，对交联胶原蛋白具有特异性。在初步数据中，我们已经证明 Gd-Hyd 可以准确检测小动物模型中的肾、肝和肺纤维化。由于LOX介导的胶原交联是活动性疾病的一个方面，我们的假设是LOX介导的胶原交联的分子成像准确地反映了肾纤维化，因此可用于检测肾纤维化并监测疾病进展和对治疗的反应。 这些研究的重要性怎么强调都不为过，因为 CKD 是一个主要的全球健康问题。我们具体目标的实现将带来一种新的方法，用于识别疾病进展和生存不良的高风险纤维化患者，并监测抗纤维化治疗的反应。