Imaging beta cell function in vivo with a Zinc responsive MRI contrast agent

使用锌响应 MRI 造影剂对体内 β 细胞功能进行成像

基本信息

批准号：
8913952
负责人：
Dean Sherry
金额：
$ 34.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-19 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913952
关键词：
Abdomen Age Animals Antibodies Attention Beta Cell Biodistribution Biological Process Bolus Infusion Cell physiology Cells Chronic Disease Clinical Complex Contrast Media Data Development Diabetes Mellitus Diet Disease Progression Extracellular Space Family suidae Fatty acid glycerol esters Functional Magnetic Resonance Imaging Glucose Goals Histologic Human Image Imaging Device In Vitro Injection of therapeutic agent Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Intervention Ions Kinetics Laboratory Rat Lead Life Style Magnetic Resonance Imaging Measurement Measures Methods Miniature Swine Modeling Molecular Weight Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Pancreas Pathogenesis Patients Phase Positron-Emission Tomography Process Protocols documentation Radiolabeled Rattus Recovery Research Resolution Slice Solid Streptozocin Technology Testing Therapeutic Thermodynamics Tissues Toxic effect Translating Translations United States National Institutes of Health Water Zinc base cellular imaging diabetic diabetic patient feeding functional decline imaging agent imaging modality in vivo insulin secretion islet manufacturing process molecular imaging non-diabetic non-invasive imaging novel radiotracer research study response sensor small molecule type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Type II diabetes is chronic disease characterized by temporal loss of beta-cell function and gradual insulin deficiency. Despite years of intensive research into the mechanisms of -cell functional decline, progress in understanding the pathogenesis of diabetes has been hampered by our inability to monitor the fate of -cells during progression of the disease or during therapeutic recovery. Although various molecular imaging approaches have been demonstrated in vitro, non-invasive imaging of -cell mass and function in vivo remains elusive. Although a few antibodies and small molecules that target the -cell are showing promise for monitoring -cell mass by positron emission tomography (PET), the preferred imaging modality for detecting biological function continues to be magnetic resonance imaging (MRI) because it is more widely available clinically and offers the much greater image resolution. However, novel MRI agents that respond to -cell function are sparse and only a few have been applied in vivo. We recently demonstrated in control mice, in STZ-treated mice, and in mice fed a high fat diet over a period of sixteen weeks that the low molecular weight Zn2+ sensor molecule, GdDOTA-diBPEN, enhances the pancreas after a bolus injection of glucose to initiate glucose stimulated insulin secretion (GSIS). Other tissues surrounding the pancreas are not enhanced by the agent at the low concentration provided. The pancreas is also not enhanced in the absence of the glucose bolus nor is it enhanced in animals lacking -cells (STZ-treated animals). These observations are consistent with the hypothesis that this agent senses release of Zn2+ from pancreatic -cells only during glucose stimulated insulin secretion (GSIS). Images of mice collected over a prolonged period of high-fat (60%) feeding show dramatic contrast enhancement throughout the abdomen, consistent with expansion of pancreatic -cell mass during progression of type II diabetes. In this project, we will optimize the protocol for delivery of glucose and the agent for imaging -cell function, image Zn2+ release during both the fast and slow phases of insulin secretion, image -cell function in rat models of type I and type II diabetes, and image -cell function in Ossabaw mini-pigs using a clinical 3T scanner. Our goal is to determine the general utility of this novel MRI agent for imaging -cell function in anticipationof translating this technology to clinical imaging.

描述（由申请人提供）：II 型糖尿病是一种慢性疾病，其特征是 β 细胞功能暂时丧失和胰岛素逐渐缺乏。尽管多年来对β细胞功能衰退的机制进行了深入研究，但由于我们无法在疾病进展或治疗恢复期间监测β细胞的命运，因此阻碍了对糖尿病发病机制的理解。尽管各种分子成像方法已在体外得到证实，但体内细胞质量和功能的非侵入性成像仍然难以实现。尽管一些靶向细胞的抗体和小分子有望通过正电子发射断层扫描 (PET) 监测细胞质量，但检测生物功能的首选成像方式仍然是磁共振成像 (MRI)，因为它的应用范围更广。临床上可用，并提供更高的图像分辨率。然而，对细胞功能做出反应的新型 MRI 试剂很少，并且只有少数已在体内应用。我们最近在对照小鼠、STZ 处理的小鼠以及喂食高脂肪饮食 16 周的小鼠中证明，低分子量 Zn2+ 传感器分子 GdDOTA-diBPEN 在推注葡萄糖后可增强胰腺功能，从而增强胰腺功能。启动葡萄糖刺激的胰岛素分泌（GSIS）。所提供的低浓度药剂不会增强胰腺周围的其他组织。在没有葡萄糖丸的情况下，胰腺也不会增强，在缺乏β细胞的动物（STZ治疗的动物）中，胰腺也不会增强。这些观察结果与该试剂仅在葡萄糖刺激的胰岛素分泌 (GSIS) 期间感知胰腺细胞释放 Zn2+ 的假设一致。长期高脂肪 (60%) 喂养期间收集的小鼠图像显示，整个腹部的对比度显着增强，这与 II 型糖尿病进展期间胰腺细胞质量的扩张一致。在这个项目中，我们将优化用于成像细胞功能的葡萄糖和试剂的递送方案，在胰岛素分泌的快相和慢相期间成像Zn2+释放，I型和II型大鼠模型中的成像细胞功能使用临床 3T 扫描仪对 Ossabaw 小型猪进行糖尿病和图像细胞功能研究。我们的目标是确定这种新型 MRI 试剂在细胞功能成像方面的通用性，以期将该技术转化为临床成像。