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Renal hypoxia in the development of glomerular fibrosis

肾小球纤维化发展中的肾脏缺氧

基本信息

批准号：
9925210
负责人：
Ilknur Ay
金额：
$ 42.87万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925210
关键词：
Adult Affect Agreement Albumins American Animal Experiments Animals Antibodies Arteriosclerosis Biopsy Chronic Kidney Failure Clinical Creatinine Data Development Diabetic Nephropathy Disease Progression End stage renal failure Exercise Extravasation Family suidae Fibrosis Foundations Furosemide Future Gases Glomerular Filtration Rate Histologic Human Hypoxia Image In Vitro Inflammation Injury to Kidney Intestines Kidney Kinetics Knowledge MRI Scans Magnetic Resonance Imaging Measurement Measures Methodology Methods Microalbuminuria Modeling Morphologic artifacts Nodular glomerulosclerosis Normal Range North America Oxygen Pathogenesis Pathologic Patients Perfusion Phase Physiologic Monitoring Physiological Play Predisposition Proteins Proteinuria Protocols documentation Radiology Specialty Rattus Renal Hypertension Renal Tissue Renal function Reproducibility Role Serum Signal Transduction Societies Source Structure T2 weighted imaging Techniques Testing Time Tissues Tracer Tubular formation Urine Water Workload blood oxygen level dependent diabetic patient disease diagnosis endothelial dysfunction experimental study high risk human subject hypoperfusion improved in vivo innovation insight interstitial kidney biopsy kidney fibrosis novel preservation renal hypoxia tissue oxygenation tool urinary virtual

项目摘要

Chronic kidney diseases (CKD) affect more than 10% of adult Americans, many of whom progress into end- stage renal failure. Glomerular fibrosis occurs in early stage of virtually all types of CKD, such as diabetic and hypertensive nephropathy. To better understand the initiation and progression of CKD, in this project we study the development of glomerular fibrosis, specifically the changes of renal tissue oxygenation and perfusion in the fibrotic development. As a major determinant for renal fibrosis and injury suggested by numerous studies, renal tissue hypoxia’s role in glomerular fibrosis has not been fully elucidated with rigorous in-vivo experiments. In this project with a well-controlled rat-fibrosis model, we will measure tissue oxygenation and perfusion using innovative and precise MRI techniques, and then accurately determine the fibrosis degree by kidney biopsy. Our preliminary study found significant decreases in MRI-measured perfusion and oxygenation in rats with intermediate glomerular fibrosis. In the proposed project, we will transfer our MRI protocol from current clinical MRI scanner to a dedicated 7T small-animal scanner to further improve measurement precision, and perform the MRI and biopsy measurements on rats with mild glomerular fibrosis (days 1 to 4 after fibrosis induction). Upon completion of this project, we will understand better the relationship between glomerular fibrosis and tissue oxygenation/perfusion, and thus gain insight into the initiation of CKD. With the knowledge gained in the current project, in future studies we will track the MRI-measured physiologic parameters for diabetic patients with microalbuminuria (high risk for diabetic nephropathy), and validate the parameters’ capability in predicting diabetic nephropathy.

慢性肾脏疾病（CKD）影响超过10%的成年美国人，其中许多人进展到终末期肾病。肾功能衰竭肾小球纤维化发生在几乎所有类型的CKD的早期阶段，例如糖尿病和糖尿病肾病。高血压肾病为了更好地了解CKD的发生和进展，在本项目中，我们研究了肾小球纤维化的发展，特别是肾组织氧合和灌注的变化，纤维化的发展。作为许多研究表明的肾纤维化和损伤的主要决定因素，肾组织缺氧在肾小球纤维化中的作用尚未通过严格的体内实验完全阐明。在这个项目中，我们将使用一个控制良好的大鼠纤维化模型，创新和精确的MRI技术，然后通过肾活检准确确定纤维化程度。我们的初步研究发现，MRI测量的灌注和氧合在大鼠中显著降低，中度肾小球纤维化。在拟议的项目中，我们将把我们的MRI方案从当前的临床 MRI扫描仪升级为专用7 T小动物扫描仪，进一步提高测量精度，对轻度肾小球纤维化大鼠（纤维化诱导后1 - 4天）进行MRI和活检测量。本研究完成后，我们将更好地了解肾小球纤维化与组织氧合/灌注，从而深入了解CKD的起始。在知识上，目前的项目，在未来的研究中，我们将跟踪MRI测量的糖尿病患者的生理参数与微量白蛋白尿（糖尿病肾病的高风险），并验证参数的预测能力糖尿病肾病