Measuring metabolically active kidney tissue in autosomal dominant polycystic kidney disease

测量常染色体显性多囊肾病中代谢活跃的肾组织

• 批准号: 10281837
• 负责人: Petter M Bjornstad
• 金额: $ 24.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10281837
• 关键词: 3-Dimensional; Acetates; Address; Adenosine Triphosphate; Adult; Affect; Age; Animal Model; Automobile Driving; Autosomal Dominant Polycystic Kidney; Calcium; Cell Respiration; Chlorides; Citric Acid Cycle; Classification; Clinical Research; Consumption; Cyst; Cystic kidney; Data; Development; Disease; Drug Kinetics; End stage renal failure; Enrollment; Exhibits; Experimental Models; Fasting; Financial compensation; Glomerular Filtration Rate; Goals; Growth; Growth and Development function; Heart; Height; Hypoxia; Hypoxia Inducible Factor; Impairment; Individual; Kidney; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolism; Methodology; Methods; Mitochondria; Modeling; Motion; Na(+)-K(+)-Exchanging ATPase; Oxidative Stress; Oxygen; Oxygen Consumption; PKD1 gene; PKD2 gene; Participant; Pathway interactions; Patients; Phase; Play; Positron-Emission Tomography; Production; Renal Blood Flow; Renal Replacement Therapy; Renal function; Research; Role; Structure; System; T2 weighted imaging; Techniques; Therapeutic; Tissues; Woman; Work; imaging biomarker; imaging modality; imaging program; improved; kidney preservation; mitochondrial dysfunction; multimodality; new therapeutic target; novel; renal hypoxia; response; stem; therapeutic target

PROJECT SUMMARY / ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by development and growth of multiple cysts requiring kidney replacement therapy in 50% of patients by the age of 60 years. Animal models implicate kidney hypoxia, potentially stemming from a mismatch between increased renal energy demand and impaired substrate metabolism, as a unifying pathway in the development and progression of kidney cysts and a potential therapeutic target. Yet, a major clinical research impediment in ADPKD is a way to accurately and non-invasively determine oxygen consumption and metabolic activity of kidney tissue in affected patients. Thus, there is a need for imaging biomarkers that can differentiate and quantify metabolically active vs. inactive kidney tissue to advance our understanding of the metabolic perturbations of ADPKD and inform the development of new therapeutic targets while changes may still be reversible. In response to NOT-DK-20-034, the investigative team seeks to develop a voxel-wise pharmacokinetic positron emission tomography (PET) model that measures the clearance of 11C-acetate in every voxel of the kidney. Next, they plan to integrate 11C-acetate PET and multiparametric magnetic resonance imaging (MRI) to determine the relationships among metabolically active kidney volume, renal blood flow and cyst burden in individuals with ADPKD and preserved kidney function. To achieve these goals, the investigative team consists of experts in PET and MRI research (Drs. Bjornstad, Gitomer, Kline, Blondin, Richard and Chin), and ADPKD (Drs. Gitomer, Kline, Chonchol, and Nowak). The current work will contribute to their long-term goal to characterize and target the mechanisms underlying cyst growth in ADPKD.

项目总结/摘要： 常染色体显性遗传性多囊肾病（ADPKD）的特征是发育和生长， 60岁以上患者中50%需要肾脏替代治疗的多发性囊肿。动物模型 涉及肾脏缺氧，可能源于肾脏能量需求增加与 基质代谢受损，作为肾囊肿发展和进展的统一途径， 一个潜在的治疗目标然而，ADPKD的一个主要临床研究障碍是如何准确和 非侵入性地确定受影响患者的肾组织的耗氧量和代谢活性。 因此，需要能够区分和量化代谢活性与非活性的成像生物标志物。 肾脏组织，以促进我们对ADPKD代谢紊乱的理解，并告知 开发新的治疗靶点，而变化可能仍然是可逆的。 为了响应NOT-DK-20-034，研究小组寻求开发一种逐体素药代动力学正电子 发射断层扫描（PET）模型，用于测量肾脏每个体素中11 C-醋酸盐的清除率。 下一步，他们计划将11 C-乙酸PET和多参数磁共振成像（MRI）整合在一起， 确定代谢活性肾体积、肾血流量和囊肿负荷之间的关系， 患有ADPKD和保留肾功能的个体。为了实现这些目标，调查小组由以下人员组成： PET和MRI研究专家（Bjornstad、Gitomer、Kline、Blondin、Richard和Chin博士）和ADPKD (Drs. Gitomer、Kline、Chonchol和Nowak）。目前的工作将有助于实现他们的长期目标， 描述和靶向ADPKD囊肿生长的潜在机制。