PET tracer for imaging senescence

项目总结/摘要 衰老是一种永久性细胞周期停滞的状态，并且可以在发育（程序性）期间发生。 衰老），或由各种应激因素触发，如端粒缩短（定义为复制性 衰老）、氧化应激DNA损伤和癌基因激活（应激诱导的早衰）。 衰老细胞保持代谢活性，并分泌高浓度的信号分子进入细胞内。 组织微环境（称为衰老相关分泌表型，或SASP）。这些分泌 因子可以激活免疫系统，启动衰老细胞的清除，这有助于肿瘤的发生。 抑制、伤口愈合和组织稳态。当免疫监视不能消除衰老 细胞，它们的积累会引起炎症，并导致各种疾病，包括癌症， 代谢障碍、纤维化、糖尿病、脑部疾病、骨关节炎和肾脏疾病。 这些在衰老和疾病中的复杂而重要的作用促使人们对发展 成像方法来检测衰老细胞。许多光学成像探针已经由 靶向衰老相关的β-半乳糖苷酶（SA-b-gal）活性。然而，它们在体内的使用是有限的 这是由于光子在活体组织中的穿透性差和散射。几种SPECT、MRI和PET探头具有 据报道，它们解决了这一限制，但它们显示出差的细胞渗透性和/或敏感性。在 在PET示踪剂的情况下，它们通常缺乏有效的信号保持机制。 本研究旨在开发一种新的PET示踪剂，用于小鼠衰老的体内成像 通过靶向新型溶酶体酶并使用细胞内探针组装保留的癌症模型 战略具体目的有两个：1）合成PET示踪剂并评估其检测能力 2）在治疗诱导的衰老的动物模型中验证PET示踪剂。这 该项目将提供一种更特异、更灵敏的PET示踪剂，用于体内细胞衰老成像， 未来的人类研究。

PROJECT SUMMARY / ABSTRACT Senescence is a state of permanent cell cycle arrest, and can occur during development (programmed senescence), or be triggered by a variety of stressors, like telomere shortening (defined as replicative senescence), oxidative stress DNA damage, and oncogene activation (stress-induced premature senescence). Senescent cells remain metabolically active and secrete high concentrations of signaling molecules into the tissue microenvironment (known as Senescence-Associated Secretory Phenotype, or SASP). These secreted factors can activate immune systems to initiate clearance of senescent cells, which contribute to tumor suppression, would healing and tissue homeostasis. When the immunosurveillance fails to eliminate senescent cells, their accumulation causes inflammation and contributes to a variety of diseases, including cancer, metabolic disorders, fibrosis, diabetes, brain disorders, osteoarthritis, and kidney disease. These complex and important roles in ageing and diseases prompt extensive interest in developing imaging methods to detect senescence cells. A number of optical imaging probes have been developed by targeting senescence-associated beta-galactosidase (SA-b-gal) activity. However, their use in vivo is limited due to poor penetration and scattering photons in living tissues. Several SPECT, MRI, and PET probes have been reported to address this limitation, but they displayed either poor cell permeability and/or sensitivity. In the case of PET tracers, they generally suffer from a lack of efficient signal retention mechanism. This research proposes to develop a novel PET tracer for in vivo imaging of senescence in a mouse model of cancer by targeting a novel lysosomal enzyme and using an in celluo probe assembly retention strategy. There are two Specific Aims: 1) synthesize the PET tracer and assess its capacity to detecting senescence in cell culture; 2) validate the PET tracer in animal models of therapy induced senescence. This project would provide a more specific and sensitive PET tracer for imaging cell senescence in vivo and for future translation into human studies.