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: 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
• 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

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逐渐的胰岛素缺乏。尽管多年来深入研究的机制，细胞功能下降，在了解糖尿病的发病机制的进展受到阻碍，我们无法监测的命运，细胞在疾病的进展或治疗恢复。虽然各种分子成像方法已被证明在体外，非侵入性成像的细胞质量和功能在体内仍然难以捉摸。尽管一些靶向细胞的抗体和小分子显示出通过正电子发射断层扫描（PET）监测细胞质量的前景，但用于检测生物功能的优选成像模式仍然是磁共振成像（MRI），因为它在临床上更广泛地使用并且提供更高的图像分辨率。然而，新的磁共振成像剂，响应细胞功能是稀疏的，只有少数已在体内应用。我们最近在对照小鼠、STZ处理的小鼠和高脂肪饮食喂养的小鼠中证明了低分子量Zn 2+传感器分子GdDOTA-diBPEN在推注葡萄糖后增强胰腺以启动葡萄糖刺激的胰岛素分泌（GSIS）。胰腺周围的其他组织在所提供的低浓度下不被药剂增强。胰腺在没有葡萄糖团的情况下也没有增强，在缺乏β-细胞的动物（STZ处理的动物）中也没有增强。这些观察结果与该试剂仅在葡萄糖刺激的胰岛素分泌（GSIS）期间感测Zn 2+从胰腺细胞释放的假设一致。在长时间高脂肪（60%）喂养期间收集的小鼠图像显示整个腹部的对比度显著增强，与II型糖尿病进展期间胰腺细胞质量的扩张一致。在本项目中，我们将优化葡萄糖输送方案和细胞功能成像剂，成像胰岛素分泌快相和慢相期间的Zn 2+释放，成像I型和II型大鼠模型中的细胞功能 糖尿病，和图像细胞功能在Ossabaw小型猪使用临床3 T扫描仪。我们的目标是确定这种新的MRI试剂的一般效用，以成像细胞功能，预期将这项技术转化为临床成像。