Novel Probes for Imaging Beta Cell Mass

用于β细胞团成像的新型探针

• 批准号: 8379033
• 负责人: RALPH WEISSLEDER, MD, PHD
• 金额: $ 55.84万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8379033
• 关键词: Affinity; Autoimmune Process; Autopsy; Bacteriophages; Behavior; Beta Cell; Binding; Biological Markers; C-Peptide; Cells; Clinical Data; Collaborations; Diabetes Mellitus; Drug Kinetics; Early Diagnosis; Economics; Enzymes; Error Sources; Failure; Functional disorder; Gene Expression; Genetic; Goals; Gold; 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; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Peptide aptamers; Peptides; Phage Display; Pharmaceutical Preparations; Plasma Proteins; Positron-Emission Tomography; Protein Binding; Recording of previous events; Screening procedure; Serum; Signal Transduction; Site; Specificity; Sterile coverings; Structure; Techniques; Testing; Therapeutic; Tissues; Treatment Efficacy; aptamer; 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) 和胰岛的功能状态是评估胰岛细胞数量的关键指标 1 型糖尿病中的自身免疫破坏。 BCM 的逐渐丧失也是造成继发性心脏病的原因之一。 目前可用药物治疗 2 型糖尿病的失败（缺乏耐久性）。血清检查，例如胰岛素/C- 肽等不能可靠地测量 BCM，目前唯一接受的金标准 测量是尸检。人们普遍认为成像最终可以用于： 了解胰岛的历史和糖尿病的病理生理学，b) 实现 1 型糖尿病的早期诊断 糖尿病 (T1DM)，c) 允许监测治疗效果和持久性（包括胰岛移植）， d) 揭示可用于发现新疗法的可成像生物标志物。不幸的是，必要的 量化 BCM 的工具仍然很大程度上缺失。因此，该项目的总体目标是开发新颖的 对 p 细胞具有特异性的体内成像方法和试剂，以便非侵入性地可视化 p 细胞的目标 1 型糖尿病的自身免疫攻击。这将使用强大的库、小分子组合来完成 和遗传方法。通过与 Mathis 和 Benoist 小组的密切合作，我们将验证最 使用公认的金标准和小鼠模型的有前景的药物。具体来说，我们会询问以下问题 问题：1）新亲和配体的体内行为和假定的结合伙伴是什么？ 2） 成像信号和BCM之间有什么相关性？ 3）误差来源是什么 测量值，以及如何减少测量值？迄今为止的进展（新的荧光小鼠模型， 成像技术，如 FPT 和 IVM 以及来自屏幕的新线索将转化为显像剂） 已经很了不起了。开发的药物和策略将被设计为可临床转化，并且 应该添加到我们之前开发的有关胰岛功能障碍成像的临床数据中。