Developing imaging nanoprobes to advance prognosis of kidney fibrosis

开发成像纳米探针以改善肾纤维化的预后

• 批准号: 10574964
• 负责人: Leyuan Xu
• 金额: $ 12.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574964
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Allografting; Apoptotic; Architecture; Atherosclerosis; Atrophic; Attenuated; Biodistribution; Biopsy; CHI3L1 gene; Cd68; Cells; Chemotactic Factors; Chronic; Chronic Kidney Failure; Complex; Contrast Media; Data; Dendrimers; Deposition; Detection; Diagnosis; Diagnostic; Disease Progression; Drug Kinetics; Engineering; Evaluation; Extracellular Matrix; Failure; Fibrosis; Fluorescein; Fluorescence; Genes; Genetic Transcription; Heterogeneity; Histologic; Histology; Human; Image; Immune; In Vitro; Inflammatory; Injury; Investigation; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Kinetics; Knock-out; Label; Ligands; Macrophage; Magnetic Resonance Imaging; Malignant Neoplasms; Mannose; Modeling; Patients; Phenotype; Physiological; Play; Preclinical Testing; Premature Mortality; Prevalence; Process; Prognosis; Proteins; Renal function; Reperfusion Injury; Reporting; Role; Sensitivity and Specificity; Severities; Specificity; Techniques; Testing; Tubular formation; Vascular blood supply; biomaterial compatibility; biomedical imaging; design; follow-up; imaging modality; imaging probe; in vivo; innovation; interstitial; kidney fibrosis; mannose receptor; mathematical model; molecular imaging; mouse model; nanoparticle; nanoprobe; nanoscale; non-invasive imaging; noninvasive diagnosis; novel; optical imaging; prognostication; receptor; repaired; side effect; technology development; tissue repair; tool; ultrasound; uptake; years of life lost; zeta potential

Project Summary Chronic kidney disease (CKD) has a high global prevalence, estimated at 11-13%, and it is ranked third highest for years of life lost due to premature mortality. Interstitial fibrosis is a chronic and progressive process affecting kidneys during CKD progression, regardless of cause. It can disrupt kidney architecture, reduce blood supply, disturb renal function, and ultimately cause kidney failure. Histologically, the degree of kidney interstitial fibrosis correlates with the severity of CKD. Hence, assessment of kidney fibrosis can facilitate prognosis and guide therapy in CKD progression. Currently, biopsy remains the gold standard for assessing kidney fibrosis, but complications and limitations exist. Hence, novel noninvasive imaging probes or methods are in high demand for the evaluation and follow-up of patients with CKD. Recently, we and others have shown that macrophages play a key role in the progression of kidney fibrosis. Macrophage accumulation significantly correlates with the degree of the extent of interstitial fibrosis and tubular atrophy in the mouse models of CKD and in human kidney diseases and chronic allograft injury. Therefore, developing novel imaging probes to noninvasively assess kidney interstitial profibrotic macrophages will help diagnose and quantify kidney fibrosis, and thus be useful to prognosticate CKD progression. This proposal presents a potential shift in current approaches to develop a novel molecular imaging probe that specifically target profibrotic macrophages in the kidneys to sensitively and specifically report renal fibrosis in the course of CKD progression. Nanoparticles have become increasingly attractive as a candidate tool to serve as effective diagnostic agents to reduce undesirable systemic side effects and overcome several physical and physiological barriers following systemic administration. Among these, dendrimers have become one of the most versatile compositionally and structurally controlled nanoscale building blocks for use as contrast agents in the field of biomedical imaging. To test this hypothesis, we propose to first engineer dendrimer nanoprobes that specifically target profibrotic macrophages (Aim 1) and then to assess dendrimer nanoprobe efficacy for diagnosis and quantification of kidney fibrosis in the mouse models of CKD (Aim 2). This application will provide us the opportunity to develop innovative nanoprobes that can be tested preclinically to non-invasively report kidney fibrosis.

项目概要 慢性肾脏病（CKD）全球患病率较高，估计为11-13%，位居第三 因过早死亡而损失的生命年数最高。间质纤维化是一个慢性、进行性的过程 无论原因如何，在 CKD 进展过程中都会影响肾脏。它会破坏肾脏结构，减少血液 影响肾功能，最终导致肾衰竭。组织学上，肾间质化程度 纤维化与 CKD 的严重程度相关。因此，肾纤维化的评估可以促进预后和 指导 CKD 进展的治疗。目前，活检仍然是评估肾纤维化的金标准， 但存在复杂性和局限性。因此，新型非侵入性成像探针或方法具有很高的应用前景。 CKD 患者评估和随访的需求。最近，我们和其他人已经证明 巨噬细胞在肾脏纤维化的进展中发挥关键作用。巨噬细胞明显聚集 与 CKD 小鼠模型中间质纤维化和肾小管萎缩的程度相关 以及人类肾脏疾病和慢性同种异体移植物损伤。因此，开发新型成像探针 无创评估肾间质促纤维化巨噬细胞将有助于诊断和量化肾纤维化， 因此有助于预测 CKD 进展。该提案提出了当前的潜在转变 开发一种新型分子成像探针的方法，该探针专门针对促纤维化巨噬细胞 肾脏敏感、特异地报告 CKD 进展过程中的肾纤维化。纳米粒子 作为有效诊断剂的候选工具，以减少 不良的全身副作用，并克服全身治疗后的一些物理和生理障碍 行政。其中，树枝状聚合物已成为组成和用途最广泛的聚合物之一。 结构控制的纳米级构建块，用作生物医学成像领域的造影剂。 为了检验这一假设，我们建议首先设计专门针对促纤维化的树枝状聚合物纳米探针 巨噬细胞（目标 1），然后评估树状聚合物纳米探针对巨噬细胞的诊断和定量的功效 CKD 小鼠模型中的肾纤维化（目标 2）。该应用程序将为我们提供开发的机会 创新的纳米探针，可以进行临床前测试，以非侵入性方式报告肾纤维化。