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（由适用提供）：衰老是大多数造成大部分发病率，死亡率和医疗保健支出的慢性疾病的主要危险因素。细胞感应可能导致与年龄相关的功能障碍和慢性疾病。我们发现靶向感官细胞鼻溶剂的药物。我们预计，鼻溶剂的初始概念证明临床试验可能是针对与局部累积细胞相关的疾病，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累积的变化，以响应候选塞溶剂剂。我们的假设是，使用基于感觉细胞的不同特征的成像方法，可以在实验动物和最终在人类中检测到感觉细胞。感觉细胞的两种特性可以通过正电子发射断层扫描（PET）成像可行的检测：细胞外蛋白质聚集和糖酵解移位。目的1是基于检测由感觉细胞产生的蛋白质聚集体的成像方法。衰老细胞会产生可通过染料，匹兹堡化合物B（PIB）检测到的细胞外蛋白聚集体，以及对特定聚集的可启发性蛋白的抗体。 PIB用于细胞外骨料的PET成像，以诊断阿尔茨海默氏病。我们将优化小鼠中的PIB PET成像，在这些小鼠中我们可以通过发光或GFP可视化感官细胞，并有选择地去除这些细胞。我们将使用以下动物模型对局部感觉进行图像：1）单腿辐射，2）一种新型的感官细胞移植小鼠模型，3）APOE敲除小鼠中高脂肪诱导的主动脉斑块。 PIB PET将在去除感官细胞之前和之后以及雷帕霉素治疗前后进行，从而逆转感官的前脂肪细胞蛋白聚集体的形成。 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）和3）蛋白质聚集体，GFP+感官感知细胞和尸检时的感觉标记。目标2是根据感官细胞的代谢属性开发成像方法。糖酵解在感官细胞中增加。氟脱氧葡萄糖（FDG）PET用于检测增加的葡萄糖利用来定位癌症或追踪改变的代谢活性。为了优化FDG PET，我们将在消除体内消除感觉细胞之前和之后对小鼠进行局部感觉细胞积累的成像。我们将通过体内发光和尸检时的GFP阳性和感应标记来验证发现。我们将在施用2-脱氧葡萄糖之前和之后对小鼠进行图像，从而消除FDG摄取。我们将测试将FDG与PIB PET增强灵敏度和特异性相结合。成像方法对于在非遗传修饰的实验动物中定位体内的感官细胞积累以及人类受试者的初步原则人类试验对局部细胞感性相关疾病的初步原则人类试验的本质将非常重要。鼻溶剂可能具有变革性。需要方法来成像感觉细胞的局部积累。