Early Detection and Quantification of OA

OA 的早期检测和量化

• 批准号: 8242595
• 负责人: KAREN A. HASTY
• 金额: $ 24.52万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242595
• 关键词: Age; Aging; Animal Model; Animals; Antibodies; Area; Arthritis; Binding; Cartilage; Cavia; Clinical Protocols; Collaborations; Collagen Type II; Data; Degenerative Disorder; Degenerative polyarthritis; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Dyes; Early Diagnosis; Early identification; Effectiveness; Encapsulated; Equipment; Evaluation; Fluorescence; Fluorescent Dyes; Fluorescent Probes; Genetic; Goals; Histopathology; Human; Image; Imaging technology; Inbred Mouse; Incidence; Individual; Injection of therapeutic agent; Intervention; Joint Capsule; Joints; Keyhole Limpet Hemocyanin; Knee joint; Label; Lesion; Liposomes; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Medial; Medial meniscus structure; Methods; Modeling; Monitor; Monoclonal Antibodies; Mus; Operative Surgical Procedures; Pathology; Patients; Population; Prosthesis; Regimen; Research; Resolution; Rodent; Sampling Errors; Scanning; Severities; Severity of illness; Sorting - Cell Movement; Specificity; Staging; Surface; Synovitis; System; Technetium; Techniques; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Time; Tissues; Weight-Bearing state; articular cartilage; bone; cost; density; in vivo; indexing; innovation; joint injury; mouse model; palliative; therapeutic evaluation; tool

DESCRIPTION (provided by applicant): Treatments for the most prevalent form of arthritis, osteoarthritis (OA), currently are primarily palliative until joints become totally dysfunctional and prosthetic replacement is needed. There are numerous obstacles for developing effective OA therapy. One is the lack of good diagnostic tools for efficiently identifying early stages of the disease and monitoring its progression in small animal models typically used for therapeutic testing. Histopathological evaluation is the traditional assessment for OA, but this requires sacrifice of the animal, uses tedious subjective criteria, may contain sampling error and cannot be used for serial measurements in a single animal. Our overall goal is to establish an innovative method to identify early cartilage damage in OA and to quantitatively assess its progression in vivo. Identification of early OA would permit interventional therapy at the earliest stages of disease when the pathology may be more amenable to intervention. We propose to use monoclonal antibodies (Mab) to native type II collagen (CII) that bind damaged cartilage to identify early subclinical lesions and quantitate disease progression in OA. If successful, this will provide an inexpensive and reproducible method that can be used for diagnosis and to monitor the effects of therapy on OA progression over relatively short to intermediate time periods. We will establish the validity of our approach, using animal models of OA; a well characterized mouse model of surgical transection for destabilization of the medial meniscus (DMM) in mice, and two models of spontaneous osteoarthritis with Dunkin-Hartley guinea pigs and Str/Ort mice that share many features of human OA. We will use and compare two methods of localization of targeted fluorescent probes to damaged cartilage; MabCII labeled with near infrared emitting fluorescent (NIF) dyes and MabCII-targeted nanosomes encapsulating NIF intravenously injected into these animals. The degree of damage will be quantified using IVIS(R) imaging technology and correlated with traditional histopathological indices for the joints identified by fluorescently labeling and in collaborative studies for high resolution MRI. Our hypothesis, supported by preliminary data, is that the fluorescently labeled antibodies (NIF-MabCII) will selectively localize to joints in which the surface of articular cartilage is eroded and CII is exposed. We expect that the technique will be extremely sensitive and identify minimal cartilage damage and that larger and more advanced lesions will bind larger quantities of NIF-MabCII. We will also test the feasibility of modifying this approach for quantitative measurements with MabCII-targeted nanosomes loaded with 99mTc technetium which could be used for evaluation in patients using existing clinical protocols and available equipment. PUBLIC HEALTH RELEVANCE: Osteoarthritis is a degenerative disease of aging cartilage that typically begins as a small lesion that progressively worsens. We will use a selective monoclonal antibody to detect and measure early OA in different animal models and to target small fluorescent liposomes to damaged cartilage.

描述(申请人提供)：治疗最常见的关节炎，骨关节炎(OA)，目前主要是姑息治疗，直到关节变得完全功能障碍，需要假体置换。开发有效的骨性关节炎治疗方法有许多障碍。其一是缺乏良好的诊断工具来有效识别疾病的早期阶段，并在通常用于治疗测试的小动物模型中监测其进展情况。组织病理学评估是对骨性关节炎的传统评估，但这需要牺牲动物，使用繁琐的主观标准，可能包含抽样误差，不能用于单一动物的连续测量。我们的总体目标是建立一种创新的方法来识别OA的早期软骨损伤，并定量评估其在体内的进展。早期发现骨性关节炎将允许在疾病的最早阶段进行介入治疗，此时病理可能更易于干预。我们建议使用结合受损软骨的天然II型胶原(CII)的单抗(Mab)来识别早期亚临床病变并量化OA的疾病进展。如果成功，这将提供一种廉价和可重复性的方法，可用于诊断和监测相对较短到中间时间段内治疗对OA进展的影响。我们将建立我们方法的有效性，使用OA的动物模型；具有良好特征的小鼠手术横断内侧半月板(DMM)模型，以及Dunkin-Hartley豚鼠和Str/Ort小鼠的两个自发性骨关节炎模型，这两个模型具有许多人类OA的特征。我们将使用并比较两种定位受损软骨的靶向荧光探针的方法：MabCII标记近红外发射荧光(NIF)染料和MabCII靶向包裹NIF的纳米体经静脉注射到这些动物体内。损伤程度将使用IVIS(R)成像技术进行量化，并与通过荧光标记识别的关节的传统组织病理学指标以及在高分辨率MRI的合作研究中相关联。我们的假设得到了初步数据的支持，即荧光标记的抗体(NIF-MabCII)将选择性地定位于关节软骨表面被侵蚀和CII暴露的关节。我们预计这项技术将是极其敏感的，可以识别出最小的软骨损伤，更大和更先进的损伤将结合更多的NIF-MabCII。我们还将测试修改这一方法用于定量测量的可行性，以MabCII为靶标的纳米小体负载99mTc，可用于使用现有的临床方案和可用的设备进行患者评估。 与公共卫生相关：骨关节炎是一种老化软骨的退行性疾病，通常始于一个小病变，然后逐渐恶化。我们将使用一种选择性的单抗来检测和测量不同动物模型的早期骨性关节炎，并将小的荧光脂质体靶向受损的软骨。