Imaging for Cellular Senescence

细胞衰老成像

• 批准号: 8966806
• 负责人: JAMES L. KIRKLAND
• 金额: $ 19.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966806
• 关键词: AP20187; Abbreviations; Accounting; Adipocytes; Age; Aging; Alzheimer' s Disease; Animal Model; Animals; Antibodies; ApoE knockout mouse; Apolipoprotein E; Apoptosis; Area; Arthritis; Autopsy; Binding Proteins; Body Composition; Brain region; Breeding; Cell Aging; Cell Transplants; Cells; Characteristics; Chronic; Chronic Disease; Clinical Trials; Collection; DNA Nucleotidylexotransferase; Dasatinib; Dementia; Deoxyglucose; Detection; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Dose; Dyes; Endothelial Cells; Extracellular Protein; Fatty acid glycerol esters; Fluorescence; Functional disorder; Gait; Ganciclovir; Generations; Glucose; Glycolysis; Goals; Health Expenditures; Histologic; Human; Image; In Situ Nick-End Labeling; Insulin-Like Growth Factor I; Interleukins; Intervention; Knockout Mice; Label; Lead; Leg; Luciferases; Lung diseases; Lymphoma; Malignant Neoplasms; Metabolic; Methods; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Mus; Muscle; Myocardial Infarction; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Pittsburgh Compound-B; Plasminogen; Positron; Positron-Emission Tomography; Property; Proteins; Quercetin; Radiation; Reporter; Risk Factors; Role; Sensitivity and Specificity; Sirolimus; Site; Stroke; Testing; Therapeutic; Tissues; Transplantation; Vascular Diseases; aerobic glycolysis; age related; anaerobic glycolysis; base; beta-Galactosidase; caspase-8; cell type; cellular transduction; chemotherapy; clinical application; extracellular; fluorodeoxyglucose; grasp; human TXN protein; human subject; imaging modality; in vivo; inhibitor/antagonist; intraperitoneal; luminescence; mortality; mouse model; novel; progenitor; protein aggregate; protein aggregation; public health relevance; radiologist; release factor; response; senescence; sensory stimulus; thymidylate kinase; uptake

 DESCRIPTION (provided by applicant): Aging is the leading risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health care expenditures. Cellular senescence may contribute to age-related dysfunction and chronic diseases. We found agents that target senescent cells senolytic drugs. We anticipate that initial proof-of concept clinical trials of senolytic agents may be for disorders associated with localized accumulation of senescent cells, such as sites exposed to therapeutic radiation, pulmonary diseases, or arthritis. For these trials, it is necessary to develop methods to track changes in these accumulations in response to candidate senolytics. Our hypothesis is that senescent cells can be detected in experimental animals, and ultimately in humans, using imaging methods based on distinct characteristics of senescent cells. Two properties of senescent cells may make detection by positron emission tomographic (PET) imaging feasible: extracellular protein aggregation and glycolytic shifts. Aim 1 is to develop imaging methods based on detecting protein aggregates produced by senescent cells. Senescent cells produce extracellular protein aggregates detectible by the dye, Pittsburgh compound B (PiB), and antibodies to specific aggregation-susceptible proteins. PiB is used for PET imaging of extracellular aggregates to diagnose Alzheimer's disease. We will optimize PiB PET imaging in mice in which we can visualize senescent cells by luminescence or GFP and selectively remove these cells. We will use the following animal models to image localized senescence: 1) single leg radiation, 2) a novel senescent cell transplanted mouse model, and 3) high fat-induced aortic plaques in ApoE knockout mice. PiB PET will be conducted before and after removing senescent cells and before and after rapamycin treatment, which reverses senescent preadipocyte protein aggregate formation. PiB PET images will be correlated with: 1) luminescence, 2) function (body composition, activity, leg muscle & metabolic function), and 3) protein aggregates, GFP+ senescent cells, and senescence markers at autopsy. Aim 2 is to develop imaging methods based on the metabolic attributes of senescent cells. Glycolysis is increased in senescent cells. Fluorodeoxyglucose (FDG) PET is used to detect increased glucose utilization to locate cancers or track altered metabolic activity. To optimize FDG PET, we will image mice with localized senescent cell accumulations before and after eliminating senescent cells in vivo. We will validate findings by luminescence in vivo and GFP-positivity and senescence markers at autopsy. We will image mice before and after administering 2-deoxyglucose, which quenches FDG uptake. We will test if combining FDG with PiB PET augments sensitivity and specificity. Imaging methods will be of immense importance to localize senescent cell accumulations in vivo in non-genetically modified experimental animals as well as human subjects for initial proof-of-principle human trials of senolytics for localized cellular senescence-related diseases. Senolytic agents could be transformative. Methods are required to image localized accumulations of senescent cells.

 描述（由申请人提供）：老龄化是大多数慢性病的主要风险因素，占发病率，死亡率和医疗保健支出的大部分。细胞衰老可能导致与年龄相关的功能障碍和慢性疾病。我们发现了针对衰老细胞的药物。我们预计，衰老清除剂的初步概念验证临床试验可能是针对与衰老细胞局部积累相关的疾病，例如暴露于治疗性辐射、肺部疾病或关节炎的部位。对于这些试验，有必要开发方法来跟踪这些积累的变化，以响应候选senolytics。我们的假设是，衰老细胞可以在实验动物中检测到，并最终在人类中，使用基于衰老细胞独特特征的成像方法。衰老细胞的两个特性可能使正电子发射断层扫描（PET）成像检测可行：细胞外蛋白质聚集和糖酵解位移。目的1是发展基于检测衰老细胞产生的蛋白质聚集体的成像方法。衰老细胞产生可由染料匹兹堡化合物B（Pi B）检测的细胞外蛋白质聚集体和特异性聚集敏感蛋白质的抗体。PiB用于细胞外聚集体的PET成像以诊断阿尔茨海默病。我们将优化小鼠中的PiB PET成像，其中我们可以通过发光或GFP可视化衰老细胞，并选择性地去除这些细胞。我们将使用以下动物模型来成像局部衰老：1）单腿辐射，2）新型衰老细胞移植小鼠模型，和3）ApoE敲除小鼠中高脂肪诱导的主动脉斑块。在去除衰老细胞之前和之后以及雷帕霉素处理之前和之后进行PiB PET，雷帕霉素处理逆转衰老前脂肪细胞蛋白聚集体形成。PiB PET图像将与：1）发光，2）功能（身体组成，活动，腿部肌肉和代谢功能），以及3）蛋白质聚集体，GFP+衰老细胞和尸检时的衰老标志物相关。目的2是发展基于衰老细胞代谢特征的成像方法。衰老细胞中糖酵解增加。氟脱氧葡萄糖（FDG）PET用于检测葡萄糖利用率的增加，以定位癌症或跟踪改变的代谢活动。为了优化FDG PET，我们将在体内消除衰老细胞之前和之后对具有局部衰老细胞积聚的小鼠进行成像。我们将通过体内发光和尸检时的GFP阳性和衰老标志物来验证研究结果。我们将在给予2-脱氧葡萄糖（可抑制FDG吸收）之前和之后对小鼠进行成像。我们将测试FDG与PiB PET的结合是否增加了灵敏度和特异性。成像方法对于在非转基因实验动物以及人类受试者中定位体内衰老细胞积累对于用于局部细胞衰老相关疾病的衰老药物的初步原理验证人体试验将是极其重要的。衰老清除剂可能会带来变革。需要对衰老细胞的局部积累进行成像的方法。