Novel Imaging Probe for Early Detection of Charcot Foot

用于早期检测夏科足的新型成像探头

基本信息

批准号：
10593866
负责人：
Laura Shin
金额：
$ 40.06万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593866
关键词：
Acute Affect Age Amputation Anatomy Ankle Area Biological Biopsy Specimen Bone Diseases Bone Resorption Bone Surface California Caspase Cell Culture Techniques Cells Cellulitis Clinical Complication Confocal Microscopy Denervation Detection Diabetic Foot Diagnosis Diagnostic Imaging Disadvantaged minority Disease Progression Disease Surveillance Disease remission Doctor of Philosophy Dose Dyes Early Diagnosis Enzymes Evaluation Event Fiber Fluorescence Fluorescence Resonance Energy Transfer Fluorogenic Substrate Foot joint structure Foundations Goals Hispanic Histologic Image Imaging technology In Situ In Vitro Incubated Inflammation Inflammatory Intervention Joints Label Laboratories Lesion Limb Salvage Limb structure Link Location Maps Measures Mediating Methods Molecular Probes Monitor Morbidity - disease rate Needles Neuropathy Operative Surgical Procedures Osteoclasts Osteolysis Osteolytic Osteomyelitis Osteopenia Outcome Patient-Focused Outcomes Patients Peptides Peripheral Nervous System Diseases Persons Phase Postoperative Period Predisposition Process Reaction Reconstructive Surgical Procedures Research Resolution Risk Risk Reduction Sampling Sentinel Signal Transduction Spectrum Analysis Sterility Surgeon Surveillance Methods Symptoms Technology Testing Time Tissues Trauma United States Universities Weight-Bearing state ankle joint arthropathies bisphosphonate black patient bone bone reconstruction bone turnover cathepsin K design diagnosis standard diagnostic tool drug discovery experimental study fluorophore foot imaging probe improved improved outcome innovation joint destruction medical schools meter minimally invasive molecular imaging mortality novel novel diagnostics overexpression preservation prognostic assays prognostic tool radiological imaging scale up temporal measurement time interval tool tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Charcot neuroarthropathy (CN) is a progressive, denervation-induced degeneration of weight bearing joints. Any patient with loss of afferent proprioceptive fibers is susceptible to this degeneration. CN presents as a discrete local inflammatory reaction resulting in the sterile destruction of joint bone in the foot and ankle. The 5-year mortality in patients is as high as 28% with greater than 67% of these patients developing severe ulcerative complications that may lead to amputation. The CN inflammatory process results in localized osteopenia in a focal area of the foot or ankle causing instability and collapse when bearing weight. It is a self-limiting process which appears to be triggered by a trauma or repetitive microtrauma. Once activated, CN is characterized by resorptive osteoclastic activity leading to a progressive bone lesion. CN is often misdiagnosed as cellulitis or osteomyelitis, delaying diagnosis and increasing bone destruction. Osteolysis of bone contributes significantly to the morbidity and mortality of patients with CN and early assessment is critical to preserve function and to reduce the risk of major amputation. There are currently no prognostic tests available for early detection of CN. Cathepsin K (CatK) is a cysteine protease produced by osteoclasts that is overexpressed in many resorptive bone diseases, including CN. We have designed a novel molecular imaging probe, OFS (Osteoadsorptive Fluorogenic Substrate), to detect CatK on bone surfaces. This probe incorporates a bisphosphonate moiety to allow it to target bone with very high tissue selectivity, together with a fluorophore linked to a Förster resonance energy transfer (FRET) quenching dye by a peptide that is specifically cleaved by CatK, thereby generating a strong fluorescent signal in the presence of the enzyme. OFS thus offers a unique method to detect abnormal osteoclast-mediated bone resorption with high sensitivity. We propose to develop this highly innovative molecular probe for early detection of osteolysis and surveillance of CN by mapping OFS fluorescence in intraoperative bone samples from CN patients, using healthy bone as a control and radiography as the reference diagnostic imaging technology. If successful, the proposed research would provide the foundation for a powerful new diagnostic and prognostic tool to improve outcomes for CN patients, among whom disadvantaged minorities are disproportionately represented. The project, led by Dr. Laura Shin, DPM, PhD (expert on limb salvage, bone reconstruction related to CN, cell culture and confocal microscopy) and Dr. Charles McKenna, PhD (expert on imaging bisphosphonates), will be performed in the PIs’ laboratories at the University of Southern California’s Keck School of Medicine (Shin) and Drug Discovery Center (McKenna).

项目概要/摘要夏科神经关节病 (CN) 是一种进行性、去神经支配引起的负重关节退化。传入本体感觉纤维缺失的患者很容易出现这种 CN 退化的情况。局部炎症反应导致足部和踝关节骨无菌性破坏 5 年。患者死亡率高达 28%，其中超过 67% 的患者出现严重溃疡可能导致截肢的并发症 CN 炎症过程会导致局部骨质减少。脚或脚踝的焦点区域在负重时导致不稳定和塌陷，这是一个自限过程。 CN 似乎是由创伤或重复性微创伤触发的。导致进行性骨病变的再吸收破骨细胞活性经常被误诊为蜂窝织炎或。骨髓炎、延迟诊断和增加骨溶解有显着影响。 CN 患者的发病率和死亡率，早期评估对于保留功能和降低大截肢的风险目前尚无可用于早期发现 CN 的预后测试。组织蛋白酶 K (CatK) 是一种由破骨细胞产生的半胱氨酸蛋白酶，在许多骨吸收细胞中过表达骨疾病，包括 CN。我们设计了一种新型分子成像探针，OFS（骨吸附）荧光底物），用于检测骨表面上的 CatK 该探针包含双膦酸盐部分。使其能够以极高的组织选择性靶向骨骼，并结合与福斯特共振相关的荧光团通过被 CatK 特异性切割的肽来进行能量转移 (FRET) 猝灭染料，从而产生 OFS 存在时发出强烈的荧光信号，从而提供了一种检测异常的独特方法。我们建议开发这种高度创新的分子，具有高灵敏度的破骨细胞介导的骨吸收。术中通过绘制 OFS 荧光来早期检测骨溶解和监测 CN 的探针来自 CN 患者的骨骼样本，使用健康骨骼作为对照，并使用放射线照相作为参考诊断如果成功，拟议的研究将为强大的新成像技术奠定基础。改善 CN 患者预后的诊断和预后工具，其中弱势少数群体是该项目由 Laura Shin 博士（DPM、博士）（肢体抢救、骨骼专家）领导。与 CN、细胞培养和共焦显微镜相关的重建）和 Charles McKenna 博士（专家双磷酸盐成像），将在南加州大学的 PI 实验室中进行凯克医学院（Shin）和药物发现中心（麦肯纳）。