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，这些慢性病占发病率、死亡率和医疗保健支出的大部分。细胞衰老可能与年龄相关的功能障碍和慢性病有关。我们发现了针对衰老细胞的抗衰老药物。我们预计，最初的概念验证临床试验可能是针对与衰老细胞局部聚集相关的疾病，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蓄积物对候选感觉剂的反应变化。我们的假设是，可以使用基于衰老细胞的明显特征的成像方法，在实验动物中检测到衰老细胞，并最终在人类中检测到。衰老细胞的两个特性可能使正电子发射断层扫描(PET)成像检测成为可能：细胞外蛋白质聚集和糖酵解位移。目的1是开发基于检测衰老细胞产生的蛋白质聚集体的成像方法。衰老细胞产生可被匹兹堡化合物B(PIB)染料检测到的细胞外蛋白聚集体，以及对特定聚集敏感蛋白的抗体。PIB用于细胞外聚集体的PET成像，以诊断阿尔茨海默病。我们将优化小鼠的PIB PET成像，在这种成像中，我们可以通过发光或GFP显示衰老细胞，并选择性地移除这些细胞。我们将使用以下动物模型来成像局部衰老：1)单腿辐射，2)一种新的衰老细胞移植小鼠模型，以及3)高脂肪诱导的ApoE基因敲除小鼠的主动脉斑块。在去除衰老细胞之前和之后以及雷帕霉素治疗前后进行PIB PET，这将逆转衰老的前脂肪细胞蛋白质聚集体的形成。PIB PET图像将与：1)发光、2)功能(身体成分、活动、腿部肌肉和代谢功能)、3)蛋白质聚集体、GFP+衰老细胞和尸检中的衰老标记物相关。目标2是开发基于衰老细胞代谢属性的成像方法。糖酵解在衰老的细胞中增加。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，我们将成像小鼠在体内消除衰老细胞之前和之后局部积累的衰老细胞。我们将通过体内发光和尸检时GFP阳性和衰老标记物来验证研究结果。我们将在注射2-脱氧葡萄糖前后对小鼠进行成像，这会抑制FDG的摄取。我们将测试FDG和PIB PET联合使用是否增加了敏感性和特异性。成像方法对于定位非转基因实验动物体内衰老细胞的积累以及人类对衰老药物治疗局部细胞衰老相关疾病的初步原则性人体试验将具有极其重要的意义。感光剂可能具有变革性。需要一些方法来对衰老细胞的局部堆积进行成像。