PET tracer for imaging senescence

用于衰老成像的 PET 示踪剂

基本信息

批准号：
10727823
负责人：
Jianghong Rao
金额：
$ 23.33万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-10 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727823
关键词：
3-Dimensional Address Aging Animal Cancer Model Animal Model Autophagocytosis Biochemical Biological Brain Diseases CASP3 gene Cancer Model Cell Aging Cell Culture Techniques Cell Cycle Cell Cycle Arrest Cell Proliferation Cells Chelating Agents Chemotherapy-Oncologic Procedure Chromogenic Substrates Colonic Neoplasms Complex DNA Damage Degenerative polyarthritis Development Diabetes Mellitus Disease Doxorubicin Enzyme Kinetics Enzymes Fibrosis Fluorine Fucosidase Future Gadolinium HCT116 Cells Homeostasis Human Hydrolase Hydrolysis Image Immune system Immunofluorescence Immunologic Immunologic Surveillance In Situ In Vitro Inflammation Kidney Diseases Label Macrophage Magnetic Resonance Imaging Malignant Neoplasms Messenger RNA Metabolic Metabolic Diseases Methods Modeling Monosaccharides Oncogene Activation Oncogenes Optics Osteoclasts Oxidative Stress Penetration Peptide Hydrolases Permeability Phenotype Photons Positron-Emission Tomography Proliferation Marker Reporting Research Role Secretory Cell Sensitivity and Specificity Signal Transduction Signaling Molecule Specificity Spiders Stress Telomere Shortening Tissue Stains Tissues Tracer Translations Tumor Suppression Validation Western Blotting Work beta-Galactosidase beta-galactoside cancer imaging cell type cellular imaging chemotherapy design enzyme activity healing imaging detection imaging modality imaging platform imaging probe improved in vitro Assay in vivo in vivo imaging interest meeting abstracts mouse model nanoassembly non-invasive imaging novel optical imaging premature rational design research and development retention rate senescence single photon emission computed tomography small molecule stressor targeted treatment tumor tumor xenograft uptake

项目摘要

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.

项目概要/摘要衰老是细胞周期永久性停滞的一种状态，可能发生在发育过程中（程序化的）衰老），或由各种压力源触发，例如端粒缩短（定义为复制性）衰老）、氧化应激 DNA 损伤和癌基因激活（应激诱导的过早衰老）。衰老细胞保持代谢活跃并分泌高浓度的信号分子到组织微环境（称为衰老相关分泌表型，或 SASP）。这些分泌的因子可以激活免疫系统，开始清除衰老细胞，从而导致肿瘤抑制、愈合和组织稳态。当免疫监视无法消除衰老时细胞，它们的积累会引起炎症并导致多种疾病，包括癌症，代谢紊乱、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复杂而重要的作用引起了人们对开发检测衰老细胞的成像方法。研发了多种光学成像探头靶向衰老相关的 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由于活体组织中光子的穿透性和散射性差。多种 SPECT、MRI 和 PET 探头据报道可以解决这一限制，但它们表现出较差的细胞渗透性和/或敏感性。在就 PET 示踪剂而言，它们通常缺乏有效的信号保留机制。本研究拟开发一种新型 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件保留来建立癌症模型战略。有两个具体目标：1）合成 PET 示踪剂并评估其检测能力细胞培养中的衰老； 2) 在治疗诱导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和未来转化为人类研究。