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）的全球患病率很高，估计为11-13％，排名第三 由于过早死亡而失去了多年的生命。间质纤维化是一个慢性和渐进的过程 无论原因如何，都会影响CKD进展过程中的肾脏。它会破坏肾脏建筑，减少血液 供应，干扰肾功能，并最终导致肾脏衰竭。在组织学上，肾脏间隙的程度 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 CKD进展中的指导疗法。目前，活检仍然是评估肾脏纤维化的黄金标准， 但是存在并发症和局限性。因此，新型的无创成像探针或方法很高 对CKD患者评估和随访的需求。最近，我们和其他人表明 巨噬细胞在肾纤维化的进展中起关键作用。巨噬细胞的积累显着 与CKD小鼠模型中的间质纤维化和管状萎缩程度相关 以及人类肾脏疾病和慢性同种异体移植损伤。因此，将新颖的成像探针开发到 非侵入性评估肾脏间质纤维巨噬细胞将有助于诊断和量化肾脏纤维化， 因此，对于预测CKD的进展很有用。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 肾脏在CKD进展过程中敏感，特别是报告肾纤维化。纳米颗粒 作为候选工具，越来越有吸引力，可以作为有效诊断剂来减少 全身性副作用不良的系统副作用，并克服了系统性后的几个物理和生理障碍 行政。其中，树枝状聚合物已成为最通用的作曲之一，并且 结构控制的纳米级构建块作为生物医学成像领域的对比剂。 为了检验这一假设，我们建议对特定针对纤维化的纳米探针进行第一批工程型纳米探针 巨噬细胞（AIM 1），然后评估树枝状聚合物纳米探针的疗效，以诊断和定量 CKD小鼠模型中的肾纤维化（AIM 2）。该应用程序将为我们提供开发的机会 可以临时测试以非侵入性报告肾脏纤维化的创新纳米探针。