Novel Probes for Imaging Beta Cell Mass

β细胞质量(BCM)和胰岛功能状态是评估急性胰腺炎程度的关键指标 1型糖尿病患者的自身免疫破坏。BCM的渐进性损失也是次要原因 目前可用的药物在2型糖尿病中失效(缺乏持久性)。血清测试，如胰岛素/C- 多肽等不能可靠地测量BCM，目前是唯一被接受的金标准 测量就是尸检。人们普遍认为，成像最终可以用来更好地 了解胰岛病史和糖尿病的病理生理学，b)能够早期诊断1型 糖尿病(T1 DM)，c)允许监测治疗效果和持久性(包括胰岛移植)， 以及d)揭示有助于发现新疗法的可成像生物标记物。不幸的是，必要的 量化BCM的工具在很大程度上仍然缺乏。因此，该项目的总体目标是在 具有p细胞特异性的活体成像方法和试剂，以非侵入性可视化靶点 1型糖尿病患者的自身免疫性发作。这将使用强大的文库，小分子组合 和遗传方法。在与Mathis和Benoist小组的密切合作中，我们将验证大多数 前景看好的药物使用公认的黄金标准和老鼠模型。具体地说，我们将询问以下问题 问题：1)新的亲和配体的体内行为和假定的结合伙伴是什么？ 成像信号与BCM有什么关系？以及3)错误的来源是什么 测量，以及如何减少它们？迄今为止的进展(新的荧光鼠标模型， 成像技术，如FPT和IVM，以及来自屏幕的新导线，将转换为显像剂) 已经很了不起了。开发的药物和策略将被设计成可在临床上翻译，以及 应该会增加我们之前开发的关于胰岛功能障碍的成像临床数据。

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.