Human Islet Antigen Discovery and Imaging

描述(由申请人提供)： 这项建议的总体目标是继续努力开发和验证适合于胰岛移植和/或1型糖尿病(TID)背景下的人胰岛成像的试剂和方法。内分泌胰腺的功能成像一直很困难，部分原因是朗格汉斯胰岛和外分泌胰腺具有许多生理作用和细胞类型。在过去的一年中(10/2002-2/2004)，我们使用转录图谱获得了人类胰岛组织、人类外分泌胰腺组织和其他组织表达的基因图谱。利用新的信息学技术，我们已经确定了以前被认为仅限于神经元和神经内分泌组织的胰岛上以前未被识别的候选标记。这些数据清楚地揭示了胰岛细胞与神经和神经内分泌细胞之间特定的分子/功能重叠，使我们现在能够利用大量的经验和研究，这些经验和研究集中在中枢神经系统的功能成像上。基于我们在识别胰岛特异性标志物方面所做的努力，我们现在提出，用PET放射性配体靶向β细胞囊泡单胺转运体2型(VMAT2)将提供对β细胞质量和功能的定量测量。我们有三个具体目标，旨在提供必要的临床前数据，尽可能方便地通过VMAT2靶向进行胰岛成像进入临床试验。在具体目标一中，我们概述了在我们的PET化学实验室建立VMAT2配体放射合成的必要步骤。具体目的二旨在扩大我们对β细胞表达的囊泡单胺转运体2型的超微结构和细胞生物学的理解。在具体目标3中，我们概述了一系列旨在证明原理的糖尿病和胰岛移植动物模型的研究(即VMAT2靶向提供了有助于管理和研究人类1型糖尿病和胰岛移植的β细胞量的定量测量)。我们已经召集了一个由基础细胞生物学家、移植外科医生和核医学专家组成的跨学科研究团队，共同的目标是开发成像试剂和技术，将胰岛与周围环境区分开来，并提供对其质量的定量测量。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to continue our efforts in developing and validating reagents and methods suitable for imaging human islets in the context of islet transplantation and/or type 1 diabetes (TID). Functional imaging of the endocrine pancreas has been difficult, in part because of the many physiologic roles and cell types that characterize the Islets of Langerhans and the exocrine pancreas. During the past year (10/2002- 2/2004) we have used transcript profiling to obtain a map of the genes expressed by human islet tissue, human exocrine pancreas tissue, and other tissues. Using novel informatics techniques we have identified previously unrecognized candidate markers on islets previously thought to be restricted to neuronal and neuroendocrine tissues. This data has clearly revealed specific molecular/functional overlaps between islet cells and cells of neural and neuroendrocrine lineage, allowing us to now take advantage of a large body of experience and research that has focused on functional imaging of the CNS. On the basis of our efforts in identifying islet specific markers we now propose that targeting beta cell vesicular monoamine transporters, type 2 (VMAT2) with PET radioligands will provide quantitative measurements of beta cell mass and function. We have three specific aims that together are designed to provide the necessary preclinical data to move islet imaging via VMAT2 targeting into clinical trials as expediently as possible. In specific aim one we outline the necessary steps to establish the radiosynthesis of VMAT2 ligands in our PET chemistry laboratory. Specific aim two focuses on expanding our understanding of the ultrastructural and cell biology of vesicular monoamine transporters type 2 as expressed in beta cells. In specific aim three we outline a series of studies in animal models of diabetes and islet transplantation designed to show proof of principle (i.e VMAT2 targeting provides quantitative measurements of beta cell mass useful for the management and study human type 1 diabetes and islet transplantation). We have drawn together an interdisciplinary research team of basic cell biologists, transplant surgeons and experts in nuclear medicine with the common goal of developing of imaging reagents and techniques that distinguish islets from its surroundings and provide quantitative measurements of their mass.