Molecular Imaging of Renal Fibrogenesis

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)探头，用于无创的、肾脏纤维化的分子成像。肾脏纤维化是所有慢性肾脏疾病(CKD)的标志。据估计，目前全球有5亿人患有慢性肾脏病，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。在美国，ESRD的发病率在过去25年中翻了一番，事实上，CKD和ESRD的治疗在2005年占到了医疗保险费用的27%(600亿美元)。临床研究表明，终末期肾病与肾脏纤维化程度有很强的相关性。肾纤维化的量化可以预测CKD患者肾功能的长期结果，也可以用来监测对新的抗纤维化治疗的反应。目前，活检是诊断肾纤维化的金标准。然而，活组织检查不适合于监测CKD患者的疾病进展，因为它是侵入性的，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的进展是一个重大的未得到满足的医学需求。这项建议是对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》的响应。特别是，它满足了对“检测和测量器官纤维化的新的微创成像方法”和“检测纤维化的变化，量化进展、稳定和/或随时间消退”以及“将纤维化状态与器官功能障碍、恢复和/或消退相关联”的特殊需求。肾功能随着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赖氨酰氧化酶(LOX)，赖氨酰氧化酶是胶原纤维的交联物。最近，我们开发了一种原型小分子磁共振(MR)探针，称为Gd-hyd，对交联型胶原具有特异性。在初步数据中，我们已经证明Gd-HYD可以准确地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脏纤维化的发生，因此可以用于检测肾脏纤维化，监测疾病进展和治疗反应。这些研究的重要性怎么强调都不为过，因为慢性肾脏病是一个重大的世界性健康问题。我们特定目标的实现将导致一种新的方法，用于识别具有疾病进展和低存活率的高危纤维化患者，并监测抗纤维化治疗的反应。

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.