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Cellular Senescence Network: New Imaging Tools for Arthritis Imaging

细胞衰老网络：关节炎成像的新成像工具

基本信息

批准号：
10493340
负责人：
Heike Elizabeth Daldrup-Link
金额：
$ 51.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10493340
关键词：
3-Dimensional Affect Age Animal Model Arthritis Atlases Attenuated Autoradiography Biological Biological Markers Bone Marrow Cartilage Cartilage Matrix Cartilage injury Cell Aging Cell Cycle Cell Cycle Arrest Cell division Cells Characteristics Chondrocytes Chronic Communities Data Defect Degenerative Disorder Degenerative polyarthritis Detection Diagnosis Diagnostic tests Direct Costs Disease Progression Enzymes Event Facilities and Administrative Costs Femur Flow Cytometry Fluorine Galactosidase Goals Health Hip Osteoarthritis Hospitalization Human Human Volunteers Hyaline Cartilage Image Imaging Device Imaging technology Immunohistochemistry In Situ Individual Infection Inflammation Inflammatory Intravenous Investigation Joints Label Lead Link Magnetic Resonance Imaging Malignant Neoplasms Maps Measures Medical Care Costs Medical Imaging Monitor Morbidity - disease rate Mus Musculoskeletal Musculoskeletal Diseases Natural regeneration Outpatients Oxidative Stress Pain Pathogenesis Patients Phase Phase I Clinical Trials Phenotype Play Positron-Emission Tomography Process Production Proteins Reactive Oxygen Species Reference Standards Reporter Genes Research Resolution Rheumatoid Arthritis Rodent Role Sensitivity and Specificity Signal Transduction Source Specimen Standardization Stress Synovial Cell Synovial Membrane System Techniques Telomere Shortening Testing Therapeutic Thick Time Tissues Trauma United States Visit age related arthropathies articular cartilage base bone cartilage repair clinically translatable cytokine disability early childhood first-in-human fluorescence imaging glycation healing human tissue hydrophilicity imaging approach imaging biomarker improved in situ imaging in vivo intravenous administration intravenous injection joint injury lost earning macrophage mouse model musculoskeletal disorder diagnosis novel novel strategies prevent radiotracer response senescence tissue mapping tissue repair treatment response uptake

项目摘要

Cellular Senescence Network: New Imaging Tools for Arthritis Imaging Senescent cells play a key role in the pathogenesis of major musculoskeletal diseases, such as chonic inflammatory joint disorders, rheumatoid arthritis (RA) and osteoarthritis (OA). Cellular senescence in articular joints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhanced production of inflammatory cytokines, which in turn perpetuates joint damage and leads to significant morbidities of afflicted patients. It has been recently discovered that clearance of senescent cells by novel “senolytic” therapies can attenuate the chronic inflammatory microenvironment of RA and OA, and thereby, prevent further disease progression and support healing processes. In order to identify patients who might benefit from these new senolytic therapies and to monitor therapy response, there is a significant unmet need in identifying and mapping of senescent cells in articular joints and related musculoskeletal tissues. To fill this gap, we propose to develop a new imaging biomarker that will significantly improve our capabilities to identify and characterize senescent cells in human musculoskeletal tissues. We have generated exciting preliminary data that show that 3-D-galacto-2-nitropyridine (PyGal), a known hydrophilic b-gal substrate, can be labeled with 18F-fluorine. Upon intravenous injection, 18F-PyGal enters senescent cells and is selectively cleaved by b- galactosidase, a senescence-specific enzyme in these cells. The trapped radiotracer can be detected with positron emission tomography (PET) and autoradiography, thereby serving as an imaging biomarker for senescent cells. We propose to introduce 18F-PyGal as the first clinically translatable radiotracer which can detect senescent cells in vivo, in bones and joints of animal models and human volunteers. In the initial UG3 phase of our project, we will demonstrate proof-of-principle of this new imaging technology in a mouse model of RA and a large animal model of OA. In the subsequent UH3 phase, we will scale, optimize and validate 18F-PyGal PET for mapping human tissues, first in human joint specimen and second in a first-in- human phase I clinical trial. At the end of the UH3 phase, we will have delivered a novel imaging tool that can visualize and quantify the presence and distribution of senescent cells in multiple musculoskeletal tissues directly, non-invasively and longitudinally in vivo. Results will be catalogized in a planned senescence cell atlas and shared with the cellular senescence network. Our 18F-PyGal-PET imaging tool will significantly improve upon state-of-the-art imaging technologies for the diagnosis of musculoskeletal disorders, can be integrated with other imaging technologies, such as MRI, and is ultimately capable of being scaled to map senescent cells in multiple human tissues in a high-throughput fashion. Since 18F-PyGal targets senescent cells in multiple different tissues and can be easily imaged with widely available medical imaging technologies, our proposed new senescence imaging biomarker can be expected to be used widely by tissue mapping centers and relevant research communities.

细胞衰老网络：关节炎成像的新成像工具衰老细胞在慢性肌肉骨骼疾病等主要肌肉骨骼疾病的发病机制中发挥着关键作用炎症性关节疾病、类风湿性关节炎（RA）和骨关节炎（OA）。关节细胞衰老关节代表局部细胞对持续压力的反应，导致细胞周期停滞并增强炎症细胞因子的产生，进而使关节损伤永久化并导致显着的患病患者的发病情况。最近发现，新的清除衰老细胞的方法 “senolytic”疗法可以减轻 RA 和 OA 的慢性炎症微环境，从而，防止疾病进一步进展并支持愈合过程。为了识别可能的患者从这些新的 senolytic 疗法中获益并监测治疗反应，存在显着的未满足需求识别和绘制关节和相关肌肉骨骼组织中衰老细胞的图谱。为了填补这个差距，我们建议开发一种新的成像生物标志物，这将显着提高我们识别的能力并表征人类肌肉骨骼组织中的衰老细胞。我们已经产生了令人兴奋的初步结果数据显示 3-D-半乳糖-2-硝基吡啶 (PyGal)（一种已知的亲水性 b-gal 底物）可以被标记与 18F-氟。静脉注射后，18F-PyGal 进入衰老细胞并被 b-选择性裂解半乳糖苷酶，这些细胞中的一种衰老特异性酶。捕获的放射性示踪剂可以用以下方法检测：正电子发射断层扫描（PET）和放射自显影，从而作为成像生物标志物衰老细胞。我们建议引入 18F-PyGal 作为第一个临床可翻译的放射性示踪剂，可以检测动物模型和人类志愿者体内、骨骼和关节中的衰老细胞。在在我们项目的初始 UG3 阶段，我们将在 RA 小鼠模型和 OA 大型动物模型。在后续的UH3阶段，我们将进行规模化、优化并验证 18F-PyGal PET 用于绘制人体组织图谱，首先是在人体关节样本中，其次是在首创中人体 I 期临床试验。在 UH3 阶段结束时，我们将提供一种新颖的成像工具，可以可视化和量化多个肌肉骨骼组织中衰老细胞的存在和分布直接、非侵入性、纵向地在体内进行。结果将编入计划的衰老细胞图谱中并与细胞衰老网络共享。我们的 18F-PyGal-PET 成像工具将显着改进基于用于诊断肌肉骨骼疾病的最先进的成像技术，可以集成与其他成像技术（例如 MRI）相结合，最终能够缩放以绘制衰老细胞图以高通量方式在多个人体组织中。由于 18F-PyGal 以多种方式靶向衰老细胞不同的组织，并且可以使用广泛使用的医学成像技术轻松成像，我们的提出的新衰老成像生物标志物有望通过组织作图得到广泛应用中心和相关研究团体。