Novel Probes for Imaging Beta Cell Mass

用于β细胞团成像的新型探针

• 批准号: 7579406
• 负责人: RALPH WEISSLEDER, MD, PHD
• 金额: $ 54.07万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579406
• 关键词: Affinity; Aging; Autoimmune Diseases; Autoimmune Process; Autopsy; Bacteriophages; Behavior; Beta Cell; Binding; Biological Markers; C-Peptide; Cell Count; Cells; Chemistry; Clinical; Clinical Data; Collaborations; Data; Diabetes Mellitus; Drug Kinetics; Early Diagnosis; Economics; Engineering; Enzymes; Error Sources; Failure; Fluorochrome; Functional disorder; Gene Expression; Genetic; Glucose; Goals; Gold; Hand; Human; Image; Imaging Techniques; Immune; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Kidney; Label; Lead; Libraries; Ligands; Liver; Measurement; Measures; Methods; Modeling; Monitor; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Peptide aptamers; Peptides; Phage Display; Pharmaceutical Preparations; Plasma Proteins; Positron-Emission Tomography; Protein Binding; Proteins; Recording of previous events; Screening procedure; Serum; Signal Transduction; Site; Specificity; Sterile coverings; Structure; Techniques; Testing; Therapeutic; Tissues; Treatment Efficacy; Validation; aptamer; base; carboxypeptidase H; combinatorial; design; imaging modality; imaging probe; in vivo; insight; islet; lipophilicity; mouse model; novel; prognostic; research study; small molecule; small molecule libraries; tool

Beta-cell mass (BCM)and the functional state of islets are critical measures in assessing the magnitude of autoimmune destruction in type 1 diabetes. Progressive loss of BCM is also responsible for the secondary failure of currently available drugs (lack of durability) in type 2 diabetes. Serum tests such as insulin/C- peptide and others do not reliably measure BCM,and currently the only accepted gold standard of measurement is autopsy. It is generally believed that imaging could ultimately be used to a) better understand the history of the islet and the pathophysiology of diabetes, b) enable earlier diagnosis of type 1 diabetes (T1DM), c) allow monitoring of therapeutic efficacy and durability (including islet transplantation), and d) reveal image-able biomarkers useful in the discovery of new therapies. Unfortunately, the necessary tools to quantify BCM are still largely missing. The overall goal of this project is therefore to develop novel in vivo imaging methods and agents with specificity for p-cells, in order to non-invasively visualize the target of autoimmune attack in type 1 diabetes. This will be done using powerful library, small-molecule combinatorial and genetic approaches. In close collaboration with the Mathis and Benoist groups, we will validate the most promising agents using accepted gold standards and mouse models. Specifically, we will ask the following questions: 1) what is the in vivo behavior and the putative binding partners of the new affinity ligands ? 2) what is the correlation between imaging signal and BCM ? and 3) what are the sources of error in measurements, and how can they be reduced ? The progress to date (newfluorescent mouse models, imaging techniques such as FPT and IVM and new leads from screens to be converted into imaging agents) has been remarkable. The developed agents and strategies will be designed to be clinically translatable, and should add to our previously developed clinical data on imaging islet dysfunction.

β细胞质量（BCM）和胰岛功能状态是评估大小的关键措施 1型糖尿病中的自身免疫性破坏。 BCM的进行性损失也是次要的原因 2型糖尿病中当前可用的药物（缺乏耐用性）的失败。血清测试，例如胰岛素/C- 肽和其他人无法可靠地测量BCM，目前是唯一接受的黄金标准 测量是尸检。通常认为成像最终可以用作a）更好 了解胰岛的病史和糖尿病的病理生理学，b）早期诊断1型 糖尿病（T1DM），c）允许监测治疗功效和耐用性（包括胰岛移植）， d）揭示可用于发现新疗法的生物标志物。不幸的是，这是必要的 量化BCM的工具仍然在很大程度上缺少。因此，该项目的总体目标是发展小说 为P细胞特异性的体内成像方法和试剂，以便非侵入性地可视化目标 1型糖尿病中的自身免疫性攻击。这将使用功能强大的库，小分子组合来完成 和遗传方法。与Mathis和Benoist团体密切合作，我们将验证最多 有前途的代理使用接受的金标准和鼠标模型。具体来说，我们将询问以下 问题：1）新亲和力配体的体内行为和假定的约束伴侣是什么？ 2） 成像信号与BCM之间的相关性是什么？ 3）错误的来源是 测量值，如何减少它们？截至 诸如FPT和IVM之类的成像技术以及将转换为成像剂的屏幕的新线索） 非常了不起。开发的代理商和策略将设计为临床翻译，并且 应该增加我们先前开发的有关成像胰岛功能障碍的临床数据。