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: 8439627
• 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/8439627
• 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 modality; in vivo; insulin secretion; islet; manufacturing process; molecular imaging; non-diabetic; 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. PUBLIC HEALTH RELEVANCE: Imaging -cell function in vivo has been an elusive goal for many years. A simple MRI Zn2+ sensor that responds to release of insulin from the pancreas is a highly significant discovery that could lead to a clinical imaging method for monitoring development of type 2 diabetes with age in human patients and, perhaps more importantly, for monitoring its reversal during pharmacological interventions or changes in dietary lifestyle.

描述(申请人提供)：II型糖尿病是一种慢性疾病，以短暂的β细胞功能丧失和渐进性胰岛素缺乏为特征。尽管多年来对-细胞功能衰退的机制进行了深入的研究，但由于我们无法监测-细胞在疾病进展或治疗恢复期间的命运，对糖尿病发病机制的理解一直受到阻碍。虽然在体外已经证明了各种分子成像方法，但在体内对细胞质量和功能的非侵入性成像仍然难以实现。尽管一些以细胞为靶标的抗体和小分子有望通过正电子发射断层扫描(PET)来监测细胞质量，但检测生物功能的首选成像方式仍然是磁共振成像(MRI)，因为它在临床上得到了更广泛的应用，并提供了更高的图像分辨率。然而，对细胞功能作出反应的新型核磁共振试剂很少，而且只有很少的药物在体内应用。我们最近在对照小鼠、STZ处理小鼠和喂食高脂饮食16周的小鼠中证明，低分子锌离子传感器分子GdDOTA-diBPEN在注射葡萄糖后增强胰腺功能，启动葡萄糖刺激的胰岛素分泌(GSIS)。在所提供的低浓度下，该药物不会增强胰腺周围的其他组织。在没有葡萄糖推注的情况下，胰腺也不会增强，在缺乏细胞的动物(STZ处理的动物)中也不会增强。这些观察结果与该药仅在葡萄糖刺激的胰岛素分泌(GSIS)过程中感觉到胰腺细胞释放锌的假设是一致的。长时间高脂肪(60%)喂养的小鼠的图像显示，整个腹部的对比度显著增强，这与II型糖尿病进展过程中胰腺细胞团块的扩张一致。在这个项目中，我们将优化葡萄糖的输送方案和成像细胞功能的试剂，胰岛素分泌快慢时的图像锌释放，以及I型和II型大鼠的图像细胞功能。 使用临床3T扫描仪对Ossabaw小型猪的糖尿病和图像细胞功能进行研究。我们的目标是确定这种新型MRI试剂在成像细胞功能方面的普遍用途，以期将这项技术转化为临床成像。 与公共健康相关：多年来，体内成像细胞功能一直是一个难以实现的目标。一个简单的对胰腺释放胰岛素做出反应的磁共振锌传感器是一项非常重要的发现，它可能导致一种临床成像方法，用于监测人类患者2型糖尿病随年龄的发展，或许更重要的是，用于监测药物干预期间或饮食生活方式变化期间的逆转。