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.

蜂窝感应网络：关节炎成像的新成像工具衰老细胞在主要肌肉骨骼疾病的发病机理中起关键作用炎症性关节疾病，类风湿关节炎（RA）和骨关节炎（OA）。关节中的细胞感应关节代表了局部细胞对持续应力的反应，从而导致细胞周期停滞并增强炎性细胞因子的产生，进而使关节损伤永存并导致显着患者受伤的病毒性。最近已经发现，新型的感觉细胞清除了感觉细胞 “鼻溶性”疗法可以减弱RA和OA的慢性炎症微环境，从而防止进一步的疾病进展并支持愈合过程。为了确定可能受益于这些新的塞溶性疗法并监测疗法反应，有很大的未满足需求在识别和映射关节关节和相关肌肉骨骼组织中的感觉细胞。填写这个差距，我们建议开发一种新的成像生物标志物，该标志物将大大提高我们的能力来识别并表征人类肌肉骨骼组织中的感觉细胞。我们引起了兴奋的初步数据表明3-D-Galacto-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进入感觉细胞，并通过B-选择性切割半乳糖苷酶，这些细胞中的一种传感特异性酶。可以检测到被困的放射性示踪剂正电子发射断层扫描（PET）和放射自显影，从而充当成像生物标志物感觉细胞。我们建议将18F-Pygal引入第一个可翻译的放射性示踪剂，可以在动物模型和人类志愿者的骨骼和关节中检测体内感觉细胞。在我们项目的初始UG3阶段，我们将在一个新成像技术的原理证明 RA的小鼠模型和大型OA动物模型。在随后的UH3阶段，我们将扩展，优化并验证18F-Pygal PET用于绘制人体组织，首先在人类关节标本中，第二在第一in- 人类I期临床试验。在UH3阶段结束时，我们将提供一个可以可视化和量化多种肌肉骨骼组织中感觉细胞的存在和分布直接，非侵入性和纵向在体内。结果将在计划的感应细胞地图集中分类并与细胞感应网络共享。我们的18F-Pygal-PET成像工具将显着改善在最先进的成像技术以诊断肌肉骨骼疾病的诊断中，可以整合使用其他成像技术（例如MRI），并最终能够缩放以映射感觉细胞以高通量方式以多种人类的时间安排。由于18f-pygal靶向多个不同的组织，可以通过广泛可用的医学成像技术轻松成像提议的新型感应成像生物标志物可以通过组织映射广泛使用中心和相关研究社区。