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

• 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
• 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

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 衰老细胞在主要的肌肉骨骼疾病的发病机制中起着关键作用，如慢性炎症， 炎性关节病症、类风湿性关节炎（RA）和骨关节炎（OA）。关节软骨细胞衰老 关节代表了局部细胞对持续压力的反应，导致细胞周期停滞和增强 炎症细胞因子的产生，这反过来又使关节损伤永久化，并导致显著的 受折磨的病人的发病率。最近已经发现，新的抗衰老药物对衰老细胞的清除是有效的。 “衰老清除”疗法可以减弱RA和OA的慢性炎症微环境，从而， 防止疾病进一步恶化并支持愈合过程。为了找出可能 为了从这些新的衰老清除疗法中受益并监测治疗反应，存在显著的未满足的需求， 在关节和相关肌肉骨骼组织中识别和绘制衰老细胞。填补这一 间隙，我们建议开发一种新的成像生物标志物，这将显着提高我们的能力，以确定 并表征人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 数据显示，3-D-半乳糖基-2-硝基吡啶（PyGal），一种已知的亲水性b-gal底物，可以被标记， 18F-氟静脉注射后，18 F-PyGal进入衰老细胞，并被B-选择性切割。 半乳糖苷酶，这些细胞中的衰老特异性酶。捕获的放射性示踪剂可以用 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作为第一个临床上可翻译的放射性示踪剂， 可以在体内、动物模型和人类志愿者的骨骼和关节中检测衰老细胞。在 在我们项目的UG 3初始阶段，我们将在 RA小鼠模型和OA大动物模型。在随后的UH 3阶段，我们将扩大规模，优化 并验证18F-PyGal PET用于绘制人体组织，首先在人体关节标本中，其次在首次 人类I期临床试验。在UH 3阶段结束时，我们将提供一种新型成像工具， 可视化和量化多种肌肉骨骼组织中衰老细胞的存在和分布 直接、非侵入性和纵向地在体内进行。结果将被编入计划的衰老细胞图谱 并与细胞衰老网络共享。我们的18F-PyGal-PET成像工具将显著改善 基于最先进的成像技术，用于诊断肌肉骨骼疾病， 与其他成像技术，如MRI，并最终能够被缩放到映射衰老细胞 以高通量的方式在多种人体组织中进行。由于18F-PyGal靶向衰老细胞， 不同的组织，可以很容易地成像与广泛可用的医学成像技术，我们的 提出的新的衰老成像生物标志物可以通过组织映射而被广泛使用 中心和相关研究社区。