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.

项目摘要 慢性肾脏病（CKD）在全球的患病率很高，估计为11- 13%，排在第三位。 由于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过程 在CKD进展期间影响肾脏，无论原因如何。它会破坏肾脏结构，减少血液 供应，干扰肾功能，并最终导致肾衰竭。组织学上，肾间质 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， 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， 但也存在复杂性和局限性。因此，新的非侵入性成像探针或方法是高度可接受的。 CKD患者的评估和随访需求。最近，我们和其他人已经表明， 巨噬细胞在肾纤维化的进展中起关键作用。巨噬细胞蓄积显著 与CKD小鼠模型中的间质纤维化和肾小管萎缩程度相关 以及人肾脏疾病和慢性同种异体移植物损伤。因此，开发新的成像探针， 非侵入性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， 因此可用于预测CKD进展。该提案带来了当前的潜在转变 开发一种新的分子成像探针的方法，该探针特异性靶向肝细胞中的促纤维化巨噬细胞， 在CKD进展过程中，肾脏敏感且特异性地报告肾纤维化。纳米颗粒 作为一种候选工具，作为有效的诊断剂， 不希望的全身副作用，并克服了全身性给药后的几种物理和生理障碍。 局其中，树枝状聚合物已成为最通用的组成和 在生物医学成像领域中用作造影剂的结构受控的纳米级结构单元。 为了验证这一假设，我们建议首先设计特异性靶向促纤维化的树枝状聚合物纳米探针， 巨噬细胞（目的1），然后评估树状聚合物纳米探针的诊断和定量功效， CKD小鼠模型中的肾纤维化（目的2）。这个应用程序将为我们提供发展的机会 创新的纳米探针，可以在临床前进行测试，以非侵入性地报告肾纤维化。