Human Islet Antigen Discovery and Imaging

人类胰岛抗原的发现和成像

• 批准号: 6954187
• 负责人: Paul E Harris
• 金额: $ 30.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954187
• 关键词: NOD mouse; SCID mouse; antibody specificity; antigen antibody reaction; bioimaging /biomedical imaging; biotechnology; clinical research; gene expression; genetic mapping; human tissue; immunoprecipitation; insulin dependent diabetes mellitus; laboratory rat; magnetic resonance imaging; method development; microarray technology; pancreas imaging /visualization; pancreatic islet function; pancreatic islet transplantation; polymerase chain reaction; positron emission tomography; reagent /indicator; surface antigens; tissue /cell culture; transplantation immunology; western blottings

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.

描述（由申请人提供）： 该提案的总体目标是继续努力开发和验证适合在胰岛移植和/或 1 型糖尿病 (TID) 背景下对人类胰岛进行成像的试剂和方法。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（10/2002-2/2004）中，我们使用转录谱分析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。使用新的信息学技术，我们在胰岛上鉴定了以前未被识别的候选标记，这些标记以前被认为仅限于神经元和神经内分泌组织。这些数据清楚地揭示了胰岛细胞与神经和神经内分泌谱系细胞之间的特定分子/功能重叠，使我们现在能够利用大量专注于中枢神经系统功能成像的经验和研究。基于我们在识别胰岛特异性标记物方面所做的努力，我们现在提出，使用 PET 放射性配体靶向 β 细胞囊泡单胺转运蛋白 2 型 (VMAT2) 将提供 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，以尽可能方便地将通过 VMAT2 靶向的胰岛成像转移到临床试验中。在具体目标一中，我们概述了在我们的 PET 化学实验室中建立 VMAT2 配体放射合成的必要步骤。具体目标之二侧重于扩大我们对 β 细胞中表达的 2 型囊泡单胺转运蛋白的超微结构和细胞生物学的理解。在具体目标三中，我们概述了一系列糖尿病和胰岛移植动物模型研究，旨在证明原理（即 VMAT2 靶向提供了 β 细胞质量的定量测量，可用于管理和研究人类 1 型糖尿病和胰岛移植）。我们组建了一支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，其共同目标是开发成像试剂和技术，将胰岛与其周围环境区分开来，并对其质量进行定量测量。