Imaging Insulin Reserves

胰岛素储备成像

基本信息

批准号：
8189918
负责人：
Maria Ildiko Zavodszky
金额：
$ 27.07万
依托单位：
GENERAL ELECTRIC GLOBAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-06 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189918
关键词：
Affect Affinity Binding Biological Biological Assay Biological Markers Biological Monitoring Cell Membrane Permeability Cell physiology Cells Chronic Clinical Clinical Research Consumption Cytoplasmic Granules Data Development Diabetes Mellitus Diagnosis Disease Early Diagnosis Early treatment Equilibrium Event Feasibility Studies Glucose Goals Health Care Costs Hyperinsulinism Image Imagery In Vitro Incidence Individual Insulin Insulin Resistance Intervention Lead Ligand Binding Ligands Literature Measurement Measures Membrane Metabolic Methods Molecular Target Monitor Non-Insulin-Dependent Diabetes Mellitus Outcome Pancreas Patients Penetration Pharmaceutical Preparations Pharmacotherapy Phase Physiology Plasma Proteins Population Positron-Emission Tomography Property Protein Binding Publishing Quantitative Evaluations Radiolabeled Research Research Personnel Risk Solubility Solutions Specificity Technology Testing Therapeutic Intervention Tissues Validation Work aqueous base diabetic diabetic patient drug development granule cell imaging modality in vivo insulin secretion interest islet pharmacokinetic model prospective protective effect radiotracer regenerative therapy response single photon emission computed tomography small molecule therapeutic target tool validation studies

项目摘要

DESCRIPTION (provided by applicant): There is an unmet need in clinical diabetes research to directly and non-invasively measure the insulin reserves of the pancreas. We propose to develop imaging agents that will allow visualization and quantitative measurement of the insulin content using PET or SPECT imaging. When combined with measurements of insulin resistance, insulin secretion response, and tissue glucose consumption, such a method will enable the comprehensive assessment of an individual's metabolic condition. This will be a useful tool in the hands of researchers for elucidating the mechanism of diabetes development. It will also provide a meaningful method for monitoring existing therapeutic interventions, for quantitative evaluation of new drug therapies (especially regenerative therapy or those treatments purported to have 2-cell protective effects), and an effective means of stratifying an already enormous population of individuals at risk for developing type 2 diabetes. Theoretical feasibility studies grounded in previously published data have indicated that our molecular target has the potential to be a good biomarker for the amount of insulin available in the pancreas. Our goal is to verify this prediction experimentally. For this we need to develop an assay which would allow us to test binding of prospective imaging agents to the target in biological context in vitro: pancreatic tissue and islets. In this proposal, we plan to optimize the properties of known small molecule ligands to our target for high affinity, low plasma protein binding and an appropriate balance between solubility and membrane penetration capability. These ligands will be radiolabeled and used to develop the cell- and tissue-based assays necessary for the first phase of target validation. Further work will be aimed at in vivo target validation studies using the ligands identified at this phase as potential imaging agents. PUBLIC HEALTH RELEVANCE: The broad goal of the proposed research is to develop imaging agents that will allow visualization and quantitative measurement of the insulin reserves of the pancreas using PET or SPECT imaging. Such a test will facilitate faster development of drugs, better choice of therapies, and will also allow diagnosis and earlier intervention, which has the potential to decrease the incidence of the disease by 30-50%. We have identified a new target for this purpose and propose to develop the necessary assays and ligands for in vitro target validation.

描述（由申请人提供）：在临床糖尿病研究中，直接且无创地测量胰腺的胰岛素储备的需求尚未得到满足。我们建议开发显像剂，使用 PET 或 SPECT 成像对胰岛素含量进行可视化和定量测量。当与胰岛素抵抗、胰岛素分泌反应和组织葡萄糖消耗的测量相结合时，这种方法将能够全面评估个体的代谢状况。这将成为研究人员手中阐明糖尿病发展机制的有用工具。它还将为监测现有治疗干预措施、定量评估新药物疗法（尤其是再生疗法或那些声称具有 2 细胞保护作用的疗法）提供有意义的方法，以及对已经庞大的个体群体进行分层的有效方法。患 2 型糖尿病的风险。基于先前发表的数据的理论可行性研究表明，我们的分子靶标有可能成为胰腺中可用胰岛素量的良好生物标志物。我们的目标是通过实验验证这一预测。为此，我们需要开发一种检测方法，使我们能够在体外测试前瞻性显像剂与生物环境中的靶标（胰腺组织和胰岛）的结合。在本提案中，我们计划优化已知小分子配体的特性，以实现高亲和力、低血浆蛋白结合以及溶解度和膜渗透能力之间的适当平衡。这些配体将被放射性标记并用于开发靶标验证第一阶段所需的基于细胞和组织的测定。进一步的工作将致力于使用在此阶段鉴定的配体作为潜在成像剂进行体内靶标验证研究。公共健康相关性：拟议研究的主要目标是开发显像剂，利用 PET 或 SPECT 成像对胰腺的胰岛素储备进行可视化和定量测量。这样的测试将有助于更快地开发药物、更好地选择治疗方法，并且还可以进行诊断和早期干预，从而有可能将疾病的发病率降低 30-50%。我们已经为此目的确定了一个新靶标，并建议开发必要的测定方法和配体以进行体外靶标验证。