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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：
10376536
负责人：
Heike Elizabeth Daldrup-Link
金额：
$ 54.95万
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/10376536
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 Cleaved cell 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 repair 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