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

• 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
• 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

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).

项目总结/摘要 Charcot神经关节病（CN）是一种进行性的、去神经引起的负重关节退行性变。任何 传入本体感受纤维缺失的患者易受这种变性的影响。CN呈现为离散的 局部炎症反应导致足部和踝关节骨的无菌破坏。5年 患者的死亡率高达28%，其中超过67%的患者发展为严重的溃疡性结肠炎。 可能导致截肢的并发症。CN炎症过程导致局部骨质减少， 脚或踝关节的局部区域，当承重时引起不稳定和塌陷。这是一个自我限制的过程 似乎是由创伤或反复的微创伤引发的一旦被激活，CN的特征在于： 导致进行性骨损伤的吸收性骨吸收活性。CN常被误诊为蜂窝织炎或 骨髓炎，延误诊断，增加骨质破坏。骨溶解显著影响 CN患者的发病率和死亡率，早期评估对于保护功能和 减少截肢的风险。目前没有可用于CN早期检测的预后测试。 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的分子成像探针OFS（Osteoadsorbent 荧光底物），以检测骨表面上的CatK。该探针结合了双膦酸酯部分， 使其能够以非常高的组织选择性靶向骨，并与连接到Förster共振的荧光团一起 能量转移（FRET）猝灭染料，从而产生一种荧光猝灭剂。 在酶存在下的强荧光信号。因此，OFS提供了一种独特的检测异常的方法 破骨细胞介导的骨吸收具有高敏感性。我们建议开发这种高度创新的分子 术中通过OFS荧光定位早期检测骨质溶解和监测CN的探针 来自CN患者的骨样本，使用健康骨作为对照，放射照相作为参考诊断 成像技术如果成功，拟议的研究将为一个强大的新的基础。 诊断和预后工具，以改善CN患者的结局，其中弱势少数群体是 不成比例的代表。该项目由Laura Shin博士领导，博士（肢体挽救专家，骨 与CN，细胞培养和共聚焦显微镜相关的重建）和Charles McKenna博士，博士（ 成像双膦酸盐），将在南加州大学的PI实验室进行 凯克医学院（新）和药物发现中心（麦肯纳）。