Developing imaging nanoprobes to advance prognosis of kidney fibrosis

项目摘要 慢性肾脏疾病(CKD)在全球范围内的患病率很高，估计为11%-13%，排名第三 这是因过早死亡而损失的生命年数中最高的。间质纤维化是一个慢性进行性的过程。 在CKD进展过程中，无论原因如何，都会影响肾脏。它可以破坏肾脏结构，减少血液 供应，扰乱肾功能，最终导致肾衰竭。组织学上，肾间质的程度 纤维化程度与CKD的严重程度相关。因此，对肾脏纤维化的评估可以促进预后和 指导慢性肾脏病进展的治疗。目前，活组织检查仍然是评估肾脏纤维化的金标准， 但也存在复杂性和局限性。因此，新的非侵入性成像探头或方法处于高水平 慢性肾脏病患者的评估和随访需求。最近，我们和其他人已经证明 巨噬细胞在肾脏纤维化的发展过程中起着关键作用。巨噬细胞显著积聚 慢性肾脏病小鼠模型肾间质纤维化程度与肾小管萎缩程度的关系 以及在人类肾脏疾病和慢性同种异体移植损伤中的作用。因此，开发新型成像探针以 无创评估肾间质纤维化的巨噬细胞将有助于诊断和量化肾纤维化， 因此对预测CKD的进展是有用的。这一提议可能会改变目前的 开发一种新型分子成像探针以特异性靶向肝纤维化前巨噬细胞的方法 肾脏可敏感和特异地报告慢性肾脏病进展过程中的肾纤维化。纳米颗粒 作为一种作为有效诊断试剂的候选工具变得越来越有吸引力 不良的全身副作用，并克服以下几个生理和生理障碍 行政管理。其中，树枝状大分子已成为组成和用途最广泛的 在生物医学成像领域中用作造影剂的结构受控纳米级构建块。 为了验证这一假设，我们建议首先设计专门针对促纤维化的树状大分子纳米探针。 巨噬细胞(目标1)，然后评估树枝状大分子纳米探针诊断和定量 慢性肾脏病小鼠模型的肾脏纤维化(目标2)。这一应用将为我们提供开发的机会 创新的纳米探针可以在临床前进行测试，以非侵入性的方式报告肾脏纤维化。

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.