Cellular Senescence Network: New Imaging Tools for Arthritis Imaging

细胞衰老网络：关节炎影像的新影像工具 衰老细胞在主要肌肉骨骼疾病的发病机制中起关键作用，如软骨症 炎症性关节疾病、类风湿性关节炎(RA)和骨关节炎(OA)。关节中的细胞衰老 关节代表局部细胞对持续压力的反应，导致细胞周期停滞和增强 产生炎性细胞因子，进而使关节损伤永久化，并导致显著 病患的患病情况。最近发现，通过新的方法清除衰老细胞 “消感”疗法可以减轻RA和OA的慢性炎症微环境，从而， 防止疾病进一步发展，并支持治愈过程。为了确定哪些患者可能 从这些新的感光疗法中受益，并监测治疗反应，有一个重大的未得到满足的需求 在识别和定位关节和相关肌肉骨骼组织中的衰老细胞方面。为了填满这个 GAP，我们建议开发一种新的成像生物标记物，它将显著提高我们识别 以及人类肌肉骨骼组织中衰老细胞的特征。我们已经产生了令人兴奋的初步结果 数据显示，3-D-半乳-2-硝基吡啶(PYGAL)，一种已知的亲水性B-GAL底物，可以被标记 用18F-氟。静脉注射后，18F-吡半乳糖进入衰老细胞，并被b-半乳糖选择性切割。 半乳糖苷酶，是这些细胞中的一种衰老特异酶。被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 衰老的细胞。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 可以检测到体内、动物模型和人类志愿者的骨骼和关节中的衰老细胞。在 在我们项目的初始UG3阶段，我们将在一个 类风湿关节炎小鼠模型和大鼠骨性关节炎动物模型。在随后的UH3阶段，我们将扩展、优化 并验证了18F-PyGal PET用于绘制人体组织图的有效性，第一次是在人类关节标本中，第二次是在第一个人的关节标本中. 人体I期临床试验。在UH3阶段结束时，我们将交付一种新的成像工具，它可以 可视化和量化衰老细胞在多个肌肉骨骼组织中的存在和分布 体内直接、非侵入性和纵向的。结果将在计划中的衰老细胞图谱中编目 并与细胞衰老网络共享。我们的18F-PyGal-PET成像工具将显著改进 基于最先进的诊断肌肉骨骼疾病的成像技术，可以集成 与其他成像技术，如磁共振成像，并最终能够被缩放以绘制衰老细胞 以高通量的方式在多个人体组织中。由于18F-PyGal以多个 使用广泛可用的医学成像技术，可以轻松地对不同组织进行成像，我们的 提出的新的衰老成像生物标志物有望通过组织图谱得到广泛应用 中心和相关研究社区。

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.