Translational imaging tools to nondestructively measure nephron mass

项目摘要 这项工作旨在通过改进诊断来改善肾病患者的预后。 肾单位质量是肾脏功能能力的量度。它的测量可能是变革性的 检测肾脏疾病的易感性和进展。然而，目前没有临床工具或测定法， 可以直接测量肾单位的质量。我们已经开发出使用新型靶向造影剂的工具 （RadioCF）使用正电子发射断层扫描（PET）直接测量肾单位质量。这项技术， RadioCF-PET有可能提供更准确的肾脏健康评估， 患者治疗的决定。RadioCF-PET也有可能用于评估， 肾移植的分配。该建议将建立RadioCF-PET测量肾单位的可行性 使用人重组形式的RadioCF（HrRadioCF）进行质量分析，以最大限度地降低毒性，控制合成， 证明了这项技术在临床应用中的潜力。我们将测量小鼠体内肾单位的质量 使用具有人重组RadioCF的RadioCF-PET。我们将使用HrRadioCF进行初步毒性研究 确定该放射性示踪剂在小鼠中的安全性，这将为II期临床试验中的安全性和有效性试验提供信息。 提议在第二阶段，我们将进行广泛的毒性研究和表征的代理，以支持 探索性研究性新药申请。RadioCF-PET的未来应用将首先集中在 活体和死亡供体移植前评估供肾以监测同种异体移植物健康 在运输过程中，然后将适用于监测移植后的移植物功能。移植评价 为住院患者使用该技术作为监测肾脏健康的新筛查工具提供了途径。这 该技术还具有监测有患肾病风险的患者，如糖尿病患者， 显示出巨大的潜在市场。

PROJECT SUMMARY This work is aimed to improve outcomes in patients with kidney disease through improved diagnostics. Nephron mass is a measure of the functional capacity of the kidney. Its measurement could be transformative in detecting susceptibility to and progression of kidney diseases. However, no clinical tools or assays currently exist to directly measure nephron mass. We have developed tools using a novel targeted contrast agent (RadioCF) to directly measure nephron mass using positron emission tomography (PET). This technology, RadioCF-PET, has the potential to provide a more accurate assessment of kidney health and aid clinical decisions for patient treatment. RadioCF-PET also has the potential to be used in the assessment and allocation of renal transplants. This proposal will establish the feasibility of RadioCF-PET to measure nephron mass using a human recombinant form of RadioCF (HrRadioCF) to minimize toxicity, control synthesis and demonstrate the potential of this technology for clinical use. We will measure nephron mass in mice in vivo using RadioCF-PET with human recombinant RadioCF. We will perform initial toxicity studies with HrRadioCF to establish the safety of this radiotracer in mice that will inform the safety and efficacy testing in a Phase II proposal. In Phase II, we will perform extensive toxicity studies and characterization of the agent to support an exploratory investigational new drug application. Future application of RadioCF-PET will first focus on the evaluation of donor kidneys before transplant in both live and deceased donors to monitor allograft health during transit, and then will be adapted to monitor graft function after transplantation. Transplant evaluation provides a pathway to in-patient use of this technology as a new screening tool to monitor kidney health. This technology also has the potential to monitor patients at risk for kidney disease, such as patients with diabetes, indicating a large potential market for impact.