Imaging for Cellular Senescence

细胞衰老成像

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：衰老是大多数慢性疾病的主要危险因素，这些疾病占发病率、死亡率和医疗保健支出的大部分，我们发现细胞衰老可能导致与年龄相关的功能障碍和慢性疾病。我们预计，针对衰老细胞的衰老药物的初步概念验证临床试验可能适用于与衰老细胞局部积累相关的疾病，例如暴露于治疗辐射的部位、肺部疾病。对于这些试验，有必要开发方法来跟踪这些积累的变化，以响应候选的衰老细胞，我们的假设是，使用基于以下的成像方法可以在实验动物中检测到衰老细胞，并最终在人类中检测到。衰老细胞的两个独特特征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。目标 1 是开发基于检测蛋白质的成像方法。衰老细胞产生的细胞外蛋白质聚集体可通过染料匹兹堡化合物 B (PiB) 检测，并且 PiB 可以用于细胞外聚集体的 PET 成像，以诊断阿尔茨海默病。小鼠 PiB PET 成像，我们可以通过发光或 GFP 观察衰老细胞，并选择性地去除这些细胞。我们将使用以下动物模型对局部衰老进行成像：1）单腿。辐射，2）新型衰老细胞移植小鼠模型，以及3）在去除衰老细胞之前和之后以及雷帕霉素治疗之前和之后，在ApoE基因敲除小鼠中进行高脂肪诱导的主动脉斑块，从而逆转衰老的前脂肪细胞蛋白聚集。 PiB PET 图像的形成将与：1) 发光、2) 功能（身体成分、活动、腿部肌肉和代谢功能）以及 3) 蛋白质聚集体相关。 GFP+ 衰老细胞和尸检中的衰老标记物目标 2 是开发基于衰老细胞糖酵解增加的成像方法，使用 FDG PET 来检测葡萄糖利用率的增加以定位癌症或追踪。为了优化 FDG PET，我们将对消除体内衰老细胞之前和之后局部衰老细胞积累的小鼠进行成像。我们将在注射 2-脱氧葡萄糖之前和之后对小鼠进行体内和 GFP 阳性标记物的成像，这会抑制 FDG 的摄取，我们将测试将 FDG 与 PiB PET 结合使用是否会增强成像方法的敏感性和特异性。定位非转基因实验动物和人类受试者体内衰老细胞的积累，以进行 senolytics 的初步原理验证人体试验局部细胞衰老相关疾病可能需要一种方法来对衰老细胞的局部积累进行成像。