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

• 批准号: 9135402
• 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
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135402
• 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; High Fat Diet; 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; 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; High Fat Diet; 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

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型糖尿病是慢性疾病，其特征是β细胞功能和逐渐胰岛素缺乏症的时间丧失。尽管对细胞功能下降的机制进行了多年的深入研究，但了解糖尿病发病机理的进展受到了我们无法监测疾病进展或治疗性康复期间 - 细胞的命运的阻碍。尽管已经在体外证明了各种分子成像方法，但细胞质量和体内功能的非侵入性成像仍然难以捉摸。尽管靶向-CELL的一些抗体和小分子通过正电子发射断层扫描（PET）显示出监测细胞质量的希望，但检测生物学功能的首选成像方式仍然是磁共振成像（MRI），因为它在临床上更广泛可用，并提供了更大的图像分辨率。然而，对响应-CELL功能的新型MRI药物很少，只有少数在体内应用。我们最近在对照小鼠，STZ治疗的小鼠和小鼠中表现出了高脂肪饮食的16周，低分子量Zn2+传感器分子GDDOTA-DIBPEN，增强了胰腺促进葡萄糖后的胰腺以启动胰糖糖刺激胰岛素的胰岛素胰岛素（GSIS）。在提供的低浓度下，药剂不会增强胰腺周围的其他组织。在缺乏葡萄糖注料的情况下，胰腺也没有增强，也没有增强缺乏细胞（STZ处理的动物）的动物。这些观察结果与以下假设一致：该试剂仅在葡萄糖刺激胰岛素分泌（GSIS）中感应Zn2+的释放。在长时间的高脂进食期间收集的小鼠的图像（60％）在整个腹部均显示出巨大的对比度增强，这与II型糖尿病进展过程中胰腺细胞质量的扩展一致。在该项目中，我们将优化用于输送葡萄糖的方案和成像 - 细胞功能的代理，图像Zn2+在胰岛素分泌的快速和慢期中释放，I型和II型大鼠模型中的图像-Cell函数 使用临床3T扫描仪在Ossabaw Mini -Pig中糖尿病和图像 - 细胞功能。我们的目标是确定这种新颖的MRI剂在预期将该技术转换为临床成像的过程中的成像功能的一般效用。