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Imaging Beta Cell Function in Vivo with Zinc Responsive MRI Contrast Agents

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：
10198907
负责人：
Dean Sherry
金额：
$ 40.5万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198907
关键词：
Accounting Affect Affinity Age Agonist Animals Beta Cell Binding Biology Bolus Infusion C-Peptide Caring Cell physiology Cells Chronic Disease Clinical Clinical Protocols Contrast Media Data Detection Development Diabetes Mellitus Disease Progression Disease Surveillance Evaluation Fluorescence Fluorescent Dyes GLP-I receptor Generations Glucose Glycosylated Hemoglobin Glycosylated hemoglobin A Goals Head Hepatic Histologic Histology Hot Spot Image Implant In Vitro Infusion procedures Insulin Insulin deficiency Ions Islets of Langerhans Macaca Magnetic Resonance Imaging Measurement Measures Metformin Modeling Monitor Monkeys Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Operative Surgical Procedures Optics Oral Pancreas Pharmaceutical Preparations Phase Plasma Protocols documentation Rattus Recovery Reporting Research Resected Rest Rodent Roentgen Rays Saline Structure of beta Cell of islet Tail Tail of pancreas Technology Therapeutic Time Tissues United States Zinc analog basal insulin base cellular imaging design detection sensitivity diabetes pathogenesis diabetic diabetic patient drug action experimental study first responder functional decline functional restoration glucose production imaging approach imaging modality imaging study improved in vivo indexing insight insulin secretion islet molecular imaging new technology non-invasive imaging nonhuman primate novel therapeutics pancreatic juice sensor synchrotron radiation treatment response

项目摘要

Type II diabetes is chronic disease characterized by temporal loss of β-cell function and gradual insulin deficiency. Despite years of intensive research into the mechanisms of β-cell functional decline, progress in understanding the pathogenesis of diabetes has been hampered by our inability to monitor the fate of β-cells during progression of the disease or during therapeutic recovery. Although various molecular imaging approaches have been demonstrated in vitro, non-invasive imaging of β-cell mass and function in vivo remains elusive. Over the past 5½ years, our lab has improved upon the original design of a responsive MRI contrast agent that responds to release of Zn2+ ions from secretory tissues and demonstrated that release of insulin and Zn2+ from pancreatic β-cells initiated by a bolus of glucose bolus can be imaged in rodents and in the macaque non-human primate. The monkey imaging studies showed that Zn2+ and insulin secretion is not uniform throughout the pancreas, consistent with known data on the non-uniform distribution of islets throughout the pancreas. A reduction in agent Zn2+ binding affinity (by ~103) resulted in a dramatic improvement in the sensitivity for detection of Zn2+ secretion from the pancreas in vivo. Furthermore, we have demonstrated that one can detect “first responder islets” as “hot spots” in the tail of the pancreas by MRI using either a low or high affinity Zn2+ sensor. In this continuation project, we will monitor first responder islets in two well-established T2DM model, the Zucker Diabetic Fatty (ZDF) rat (obese model) and the Goto-Kakizaki (GK) rat (non-obese model). Animals will be imaged every 2 weeks during progression of the disease and as they respond to clinically approved T2DM drugs. The imaging methods will be validated by independent measures of insulin content (fluorescence) and Zn2+ content by SR-XRF. Our goal is to demonstrate that β-cell function can be monitored in the head and tail regions of the pancrease reproducibly by MRI and that this technology will provide new insights into β-cell function that will catalyze development of new drugs for T2DM.

II型糖尿病是一种慢性疾病，其特征是β细胞功能的暂时丧失和渐进性胰岛素缺乏症。尽管多年来对β细胞功能的机制进行了深入的研究随着糖尿病发病率的下降，对糖尿病发病机制的理解一直受到我们的阻碍在疾病进展或治疗过程中无法监测β细胞的命运恢复。尽管在体外已经证明了各种分子成像方法，体内β细胞质量和功能的非侵入性成像仍然难以实现。在过去的5年半里多年来，我们的实验室改进了最初设计的响应性磁共振造影剂对分泌组织中锌离子的释放做出反应，并证明了胰岛素和锌离子来自胰腺β-细胞的葡萄糖团注启动可以成像啮齿动物和猕猴中的非人类灵长类。猴子的成像研究表明在整个胰腺中，锌离子和胰岛素的分泌并不均匀，这与已知数据一致。胰岛在整个胰腺的不均匀分布。试剂中锌离子的还原结合亲和力(~103)导致检测的灵敏度显著提高体内胰腺分泌的锌离子。此外，我们已经证明，一个人可以用核磁共振检查胰腺尾部的“第一反应者胰岛”作为“热点” 低或高亲和力锌离子传感器。在这个续集项目中，我们将监控第一响应者两种成熟的T2 DM模型中的胰岛：Zucker糖尿病脂肪(ZDF)大鼠(肥胖模型) 和Goto-Kakizaki(GK)大鼠(非肥胖模型)。动物将每两周进行一次成像在疾病发展过程中，当他们对临床批准的T2 DM药物有反应时。这个成像方法将通过胰岛素含量(荧光)的独立测量来验证。 SR-XRF测定锌离子含量。我们的目标是证明β细胞的功能是可以监测的在胰腺的头部和尾部区域可以通过MRI重现，这项技术将提供对β细胞功能的新见解，将催化新药的开发 T2 DM。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Using micro-synchrotron radiation x-ray fluorescence (µ-SRXRF) for trace metal imaging in the development of MRI contrast agents for prostate cancer imaging.

DOI：
10.1016/j.jtemb.2022.127054
发表时间：
2022-12
期刊：
JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
影响因子：
3.5
作者：
Dao, E.;Jordan, M. V. Clavijo;Geraki, K.;Martins, A. F.;Chirayil, S.;Sherry, A. D.;Farquharson, M. J.
通讯作者：
Farquharson, M. J.

Advances in gadolinium-based MRI contrast agent designs for monitoring biological processes in vivo.

DOI：
10.1016/j.cbpa.2018.04.006
发表时间：
2018-08
期刊：
Current opinion in chemical biology
影响因子：
7.8
作者：
Lux J;Sherry AD
通讯作者：
Sherry AD

A Responsive Magnetic Resonance Imaging Contrast Agent for Detection of Excess Copper(II) in the Liver In Vivo.

DOI：
10.1021/jacs.8b13493
发表时间：
2019-06
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Namini N Paranawithana;A. Martins;Veronica Clavijo Jordan;P. Zhao;S. Chirayil;Gabriele Meloni;A. Sherry
通讯作者：
Namini N Paranawithana;A. Martins;Veronica Clavijo Jordan;P. Zhao;S. Chirayil;Gabriele Meloni;A. Sherry

Synchrotron Radiation X-ray Fluorescence Elemental Mapping in Healthy versus Malignant Prostate Tissues Provides New Insights into the Glucose-Stimulated Zinc Trafficking in the Prostate As Discovered by MRI.

DOI：
10.1021/acs.inorgchem.9b01132
发表时间：
2019-10-21
期刊：
INORGANIC CHEMISTRY
影响因子：
4.6
作者：
Jordan, Veronica Clavijo;Al-Ebraheem, Alia;Geraki, Kalotina;Dao, Erica;Martins, Andre F.;Chirayil, Sara;Farquharson, Michael;Sherry, A. Dean
通讯作者：
Sherry, A. Dean

MRI Methods for Imaging Beta-Cell Function in the Rodent Pancreas.

啮齿动物胰腺 β 细胞功能成像的 MRI 方法。