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).

项目摘要/摘要 夏科特神经关节病(CN)是一种进行性的、由失神经导致的负重关节退行性变。任何 失去传入本体感觉纤维的患者更容易发生这种变性。CN显示为离散的 局部炎症反应导致足部和脚踝关节骨无菌破坏。五年制 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 可能导致截肢的并发症。CN炎症过程导致局限性骨量减少。 负重时脚部或脚踝的局部区域导致不稳定和塌陷。这是一个自我限制的过程。 这似乎是由创伤或重复性微创伤引发的。一旦激活，CN的特征是 骨吸收性破骨细胞活动导致进行性骨损伤。CN常被误诊为蜂窝织炎或 骨髓炎，延误诊断，增加骨质破坏。骨溶解在骨质疏松症中起重要作用 与CN患者的发病率和死亡率有关，早期评估对保护功能和 降低重大截肢的风险。目前尚无可用于早期发现CN的预后检测方法。 组织蛋白酶K(CatK)是破骨细胞产生的一种半胱氨酸蛋白酶，在许多吸收性疾病中过表达。 骨病，包括CN。我们设计了一种新型的分子成像探针OFS(OsteoDeadative) 荧光底物)，以检测骨表面的CatK。该探针剂含有部分双膦酸根 允许它以非常高的组织选择性靶向骨骼，以及与Förster共振相关联的荧光团 能量转移(FRET)通过CatK特异性切割的多肽来猝灭染料，从而产生 在酶的存在下有很强的荧光信号。因此，OFS提供了一种独特的方法来检测异常 破骨细胞介导的骨吸收具有高敏感性。我们计划开发这种高度创新的分子 术中荧光地形图早期发现骨溶解及监测CN的探讨 CN患者的骨标本，以健康骨为对照，以X线片为参照诊断 成像技术。如果成功，拟议的研究将为一个强大的新的 诊断和预后工具，以改善CN患者的预后，其中弱势少数民族是 不成比例的代表。该项目由Laura Shin博士领导，DPM，PhD(肢体保肢，骨骼专家 与CN、细胞培养和共聚焦显微镜相关的重建)和Charles McKenna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(Shin)和药物发现中心(McKenna)。